KR101131649B1 - Azolidinone-vinyl fused-benzene derivatives - Google Patents

Abstract

The present invention relates to formula (I) for the treatment and / or prevention of autoimmune diseases and / or inflammatory diseases, cardiovascular diseases, neurodegenerative diseases, bacterial or viral infections, kidney disease, platelet aggregation, cancer, graft rejection or lung damage. It relates to azolidinone-vinyl conjugated-benzene derivatives. Formula (I) wherein A, X, Y, Z, R ¹ , R ² and n are as described in the detailed description of the invention.

(I)

(I)

Description

Azolidinone-vinyl fused-benzene derivatives

The present invention relates to autoimmune disorders and / or inflammatory diseases, cardiovascular disease, neurodegenerative diseases, bacterial or viral infections, kidney disease ( Azolidinone-vinyl fused derivatives of formula (I) for the treatment and / or prevention of kidney disease, platelet aggregation, cancer, graft rejection or lung injury qenzene derivatives). Specifically, the present invention relates to substituted azoles for modulating the activity or function of the phospho-inositide-3'OH kinase family (PI3K), in particular PI3Kγ, in particular for inhibition of activity. It relates to a lidinone-vinyl conjugated benzene derivative.

Cell plasma membranes can be considered large warehouses of secondary messengers that can be incorporated into various signal transduction pathways. With regard to the function and regulation of effector enzymes in the phospholipid signaling pathway, these enzymes generate secondary messengers from membrane phospholipid pools (class I PI3 kinases (eg PI3K gamma)), Dual-specific kinase enzymes, which serve as two intramolecular regulatory mechanisms, including automatic phosphorylation: lipid kinases (phospho-inositide phosphorylation) as well as protein kinase activity known to be capable of phosphorylating different protein substrates. It means to play a role. Phospholipid signaling enzymes can be described in several ways, such as growth factors, mitogens, integrin hormones, cytokines, viruses, and neurotransmitters as described in Scheme 1 below. In response to a variety of extra-cellular signals, and also other signal molecules such as, for example, small GTPases, kinases or phosphatases (cross-talk, the original signal is second). Activated by intracellular cross-regulation where it can activate any parallel pathway that delivers signals to PI3K as a result of intra-cellular signaling.

Inositol phospholipids [Inositol phospholipids (phosphoinositide)] Intracellular signaling pathways may include signaling molecules [extracellular ligands, stimuli, receptor dimerizatioins, heterologous receptors (eg, receptor tyrosine). Delivery activity by kinases) to the G-protein linked transmembrane receptor integrated into the plasma membrane.

PI3K converts membrane phospholipid PIP (4,5) 2 into PIP (3,4,5) 3, which in turn alternates to 5'-specific phospho-inositide phosphatases. Is further converted to another 3'-phosphorylated form, so that the PI3K enzyme activity directly or indirectly acts as a second messenger in intra-cellular signal transduction. Results in the production of subtypes (3'-phosphoinositide subtypes) ( Trends Biochem Sci. 22 (7) p. 267-72 (1997) by Vanhaesebroeck B et al., Chem Rev. 101 (8) p.2365-80 (2001) by Leslie NR et al (2001); Annu Rev Cell Dev Biol . 17 p.615-75 (2001) by Katso R. et al. And Cell Mol Life Sci . 59 (5) p.761-79 ( 2002) by Toker a. Et al. Multiple PI3K isostructures categorized by catalytic subunits, control by corresponding regulatory subunits, expression patterns, and signal specific functions (p110α, β, δ, and γ) are responsible for the enzymatic reaction. Exp Cell Res. 25 (1) p.239-54 (1999) by Vanhaesebroeck B and Annu Rev Cell Dev Biol . 17 p. 615-75 (2001) by Katso R. et al].

Evolutionary conserved isoforms p110 α and β are expressed everywhere, while δ and γ are more specific in the haematopoetic cell system, smooth muscle cells, muscle cells and endothelial cells. [ Trends Biochem Sci. 22 (7) p. 267-72 (1997) by Vanhaesebroeck B et al.]. Their expression can also be regulated by inducible methods depending on the cell environment, tissue type and stimulation as well as the disease environment. To date, eight mammalian PI3Ks have been identified and largely divided into three classes (I, II and III) based on sequence homology, structure, binding partner, activation mode and in vitro substrate preference. Class I PI3K phosphorylates phosphatidylinositol (PI), phosphatidylinositol-4-phosphate, and phosphatidylinositol-4,5-biphosphate (PIP2) to form phosphatidylinositol-3-phosphate (PIP), phosphatidylinositol -3,4-biphosphate, and phosphatidylinositol-3,4,5-triphosphate, respectively. Class II PI3K phosphorylates PI and phosphatidylinositol-4-phosphate. Class III PI3Ks can only phosphorylate PI [ Trends Biochem Sci. 22 (7) p. 267-72 (1997) by Vanhaesebroeck B et al, Exp Cell Res. 25 (1) p. 239-54 (1999) by Vanhaesebroeck B et al., And Chem Rev. 101 (8) p. 2365-80 (2001) by Leslie NR et al (2001). G-protein coupled receptors modulate phosphoinositide 3'OH-kinase activity through small GTPases such as Gβγ and Ra, and consequently PI3K signaling is a power organ of cell polarity and cytoskeleton--they move cells together Provides driving force-plays an important role in creating and cooperating.

Scheme 1

As illustrated in Scheme 1 above, phosphinositide 3-kinase (PI3K) is involved in the phosphorylation of phosphatidylinositol (PtdIn) of the third carbon of the inositol ring. Phosphorylation of PtdIn to 3,4,5-triphosphate (PtdIn (3,4,5) P ₃ ), PtdIn (3,4) P _2, and PtdIn (3) P may lead to cell proliferation, cell differentiation ( cell differentiation, cell growth, cell size, cell survival, apoptosis, adsorption, cell motility, cell migration, chemotaxis, invasion, cytoskeletal rearrangement It acts as a secondary messenger in several signaling pathways, including cytoskeletal rearrangement, cell shape changes, vesicle trafficking, and metabolic pathways [ Annu Rev Cell Dev Biol , 17p 615-75 (2001) by Katso et al. and Mol Med Today 6 (9) p.347-57 (2000) by Stein RC]. Direct movement of cells towards the central gradient of the chemotactic-chemical attractant, also called chemokine, can be attributed to inflammation / autoimmune, degenerative neuropathy, angiogenesis, invasion / metastisis and Related to wound healing [ Immunol Today 21 (6) p260-4 (2000) by Wyman NP et al .; Science 287 (5455) p1049-53 (2000) by Hirsch et al .; FASEB J 15 (11) p2019-21 (2001) by Hirsch et al. and Nat Immunol. 2 (2) p 108-15 (2001) by Gerard C et al.].

Recent technological advances, using genetic approaches and pharmacological tools, respond to chemoattractant activated G-protein coupled receptor PI3-kinase, which contributes to the release of phosphorylated signaling products. This led to the identification of signaling and molecular pathways that modulate chemotaxis, which is a growth factor receptor tyrosine that phosphorylates phosphatidylinositol (PI) and derivatives phosphorylated at the 3'-hydroxyl group of its inositol ring. kinases) and viral oncoproteins (Panayotou et al., Trend Cell Biol 2 p. 358-60 (1992). However, in recent biochemical studies, class I PI3 kinase (eg class I isomer PI3Kγ), including lipids as well as protein kinase activity, has been shown to be capable of phosphorylating other proteins as substrates, including automatic phosphorylation as an intermolecular regulatory mechanism. It was found to be a dual-specific kinase enzyme that plays two roles of kinase (phospho-inositide phosphorylation) activity.

Thus, PI3-kinase activity is believed to be related to a range of cellular responses including cell growth, differentiation and apoptosis [Parker et al., Current Biology 5 p. 577-99 (1995), Yao et al., Science 267p 2003-05 (1995).

PI3-kinase appears to be involved in some aspects of leukocyte activity. p85-related PI3-kinase activity has been known to be physically related to the cytoplasmic domain of CD28, an important costimulatory molecule for T-cell activity in antigen responses [Pages et al. , Nature, 369p 327-29 (1994); Rudd, Immunity 4 p. 527-34 (1996). The activity of T cells through CD28 lowers the starting point of activity by the antigen and increases the amount and duration of proliferative responses. These effects are associated with increased transcription of several genes, including the important T-cell growth factor interleukin-2 (IL2) (Fraser et al., Science , 251 p 313-16 (1991)). Mutations in CD28 that allow longer interaction with PI3-canases do not initiate the production of IL2, which plays a critical role for PI3-kinase in T cell activation. PI3Kγ has been identified as a mediator of G beta-gamma-dependent regulation of JNK activity, and G beta-gamma is a subunit of heterotrimeric G protein [ J. Biol . Chem . 273 (5) p 2505-8 (1998). Cytoplasmic processes in which PI3K plays an important role include: inhibition of apoptosis, reorganization of actin skeleton, cardiac myocyte growth, glycogen synthase stimulation by insulin, TNFα-mediated neutrophil priming (TNFα-mediated neutrophil priming) and superoxide production, and leukocyte migration and adsorption to endothelial cells. Recently, [Immunity 16 (3) p 441-51 (2002)] PI3Kγ various G (i) - relays inflammatory signals through coupled receptor, and mast cells (mast cell) function, leukocyte stimulation in situations, in Immunology Its central role has been described to include, for example, cytokines, chemokines, adenosines, antibodies, integrins, aggregation factors, growth factors, virudes or hormones ( J. Cell Sci . 114 (Pt 16) p. 2903-10 (2001) by Lawlor Ma et al., Immunity 16 (3) p. 441-51 (2002) by Laffargue M. et al. And Curr.Opinion Cell Biol . 14 (2) p.203-13 (2002) by Stephens L. et al.)

Each member specificity inhibitor of one family of enzymes provides a valuable tool for reading the function of each enzyme. Two compounds, LY294002 and wortmannin (see below), have been widely used as PI3-kinase inhibitors. These compounds are nonspecific PI3K inhibitors because they are indistinguishable among the four members of class I PI3-kinase. For example, the IC ₅₀ value of Wortmani for each of the various Class I PI3-kinases is in the range of 1-10 nM. Similarly, the IC ₅₀ value of LY294002 for each of these PI3-kinases is about 15-20 μM [Fruman et al., An. Rev. Biochem ., 67 p. 481-507 (1998)], 5-10 [mu] M for CK2 protein kinase and some inhibitory activity for phospholipase. Watermanin is a fungal metabolite that covalently binds to the enzyme's catalytic domain and irreversibly inhibits the activity of PI3K. Inhibiting PI3K activity by Wotmani removes the continuous cellular response to extracellular factors. For example, neutrophils respond to chemokine fMet-Leu-Phe (fMLP) by stimulating PI3K and synthesizing PtdIn (3,4,5) P ₃ . This synthesis is associated with the activation of respirators bursts associated with neutrophil destruction attacking microorganisms. Neutrophil treatment with wortmannin prevents the fMLP-induced respiratory burst response [Thelen et al. PNAS 91p. 4960-64 (1994). In addition to other experimental evidence, these experiments with wortmannin have also shown that many immune weapons memories of hematopoietic lineage, especially intracellular PI3K activity of neutrophils, monocytes and other types of white blood cells, are associated with acute and chronic inflammation. It has been shown to be related to non-memory immune responses.

LY294002 Wortmanin

Based on studies using wortmannin, there is evidence that PI3-kinase function is also required for certain forms of leukocyte signaling through G-protein coupled receptors [Telen et al., Proc . Natl. Acad. Sci. USA, 91 p. 4960-64 (1994). In addition, wortmannin and LY294002 have been known to prevent neutrophil migration and superoxide release. However, as long as these compounds are not distinguished among the various isoforms, it remains unclear whether specific PI3K isoforms or isoforms are involved in these phenomena.

Azolidinone-vinyl benzene derivatives with the essential benzimidazole moieties-are described in WO 02/051409. These compounds are mentioned to inhibit telomerase and have been advocated as useful in the treatment of cancer.

Summary of the Invention

The present invention relates to autoimmune diseases and / or inflammatory diseases, cardiovascular diseases, degenerative neurological diseases, bacterial or viral infections, kidney diseases, platelet aggregation, cancer, transplantation complications, graft rejection or lung injury. To the use of an azolidinone-vinyl conjugated-benzene derivative of formula (I) and a pharmaceutically acceptable salt thereof for the preparation of a pharmaceutical composition for treatment and / or prevention,

(I)

(I)

Here, A, X, Y, Z, n, R ¹ and R ² are described in detail later in the specification. Compounds of the present invention are inhibitors of phosphato-inositide 3-kinase (PI3K), in particular phosphatoinositide 3-kinase gamma (PI3Kγ).

Detailed description of the invention

The compounds of the present invention are modulators of phosphatoinositide 3-kinase (PI3K), in particular phosphatoinositide 3-kinase gamma (PI3Kγ). When phosphatoinositide 3-kinase (PI3K) enzyme is inhibited by the compounds of the present invention, PI3K is unable to exert its enzymatic, biological and / or pharmacological effects. The compounds of the invention are therefore useful for the treatment and prevention of autoimmune diseases and / or inflammatory diseases, cardiovascular diseases, neurodegenerative diseases, bacterial or viral infections, kidney diseases, platelet aggregation, cancer, graft complications, graft rejection or lung injury. Do.

The following paragraphs provide definitions of the various chemical moieties that make up the compounds according to the invention, which definitions apply equally throughout the specification and claims of the invention and are broadly defined if not explicitly defined. To provide.

"C ₁ -C ₆ -alkyl" represents monovalent alkyl groups having 1 to 6 carbon atoms. The term is exemplified by functional groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, n-hexyl and the like.

“Aryl” refers to an unsaturated, aromatic carbocyclic group having 6 to 14 carbon atoms having a single ring (eg phenyl) or multiple condensed ring (eg naphthyl). Preferred aryls include phenyl, naphthyl, phenantrenyl and the like.

"C ₁ -C ₆ -alkyl aryl" refers to a C ₁ -C ₆ -alkyl group having aryl substituents, including benzyl, phenethyl and the like.

"Heteroaryl" refers to monocyclic heteroaromatic, or bicyclic or tricyclic fused-ring heteroaromatic gruop. Specific examples of heteroaromatic groups are optionally substituted pyridyl, pyrrolyl, furyl, thienyl, imidazolyl, oxazolyl, isoxazolyl (isoxazolyl), thiazolyl, isothiazolyl, pyrazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,3-oxadiazolyl (oxadiazolyl), 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl; 1,3,4-triazinyl, 1,2,3-triazinyl, benzofuryl, [2,3-dihydro] benzofuryl, isobenzofuryl, benzothier Benzothienyl, benzotriazolyl, isobenzothienyl, indolyl, isoindoleyl, 3H-indolyl, benzimidazolyl, imidazo [1,2-a] pyridyl (imidazo [1, 2-a] pyridyl), benzothiazolyl, benzoxazolyl, quinolizinyl, quinazolinyl, phthalazinyl, pthalazinyl, quinoxalinyl, cinnolinyl ( cinnolinyl), napthyridinyl, pyrido [3,4-b] pyridyl, pyrido [3,2-b] pyridyl, pyrido [4,3-b] pyridyl, quinolyl ), Isoquinolyl, tetrazolyl, 5,6,7,8-tetrahydroquinolyl, 5,6,7,8-tetrahydroisoquinolyl, purinyl, pterididinyl, carr Carbazolyl, xanthenyl or benzoquinolyl.

"C ₁ -C ₆ -alkyl heteroaryl" includes 2-furylmethyl, 2-thienylmethyl, 2- (1H-indol-3-yl) ethyl and the like To C ₁ -C ₆ -alkyl group having a heteroaryl substituent.

"C ₂ -C ₆ -alkenyl" refers to an alkenyl group having 2 to 6 carbon atoms and having alkenyl unsaturation at least 1 or 2 positions. Preferred alkenyl groups include ethenyl (-CH = CH ₂ ), n-2-propenyl (allyl, -CH ₂ CH = CH ₂ ) and the like.

"C ₂ -C ₆ -alkenyl aryl" refers to a C ₂ -C ₆ -alkenyl group having an aryl substituent including 2-phenylvinyl and the like.

"C ₂ -C ₆ -alkenyl heteroaryl" refers to a C ₂ -C ₆ -alkenyl group having a heteroaryl substituent including 2- (3-pyridinyl) vinyl and the like.

"C ₂ -C ₆ -alkynyl" refers to an alkynyl group having 2 to 6 carbon atoms and an alkynyl group having an alkynyl unsaturation at least in the 1-2 position; preferred alkynyl groups are ethynyl (-C≡CH), Propazyl (-CH ₂ C≡CH) and the like.

"C ₂ -C ₆ -alkynyl aryl" refers to a C ₂ -C ₆ -alkynyl group having aryl substituents, including phenylethynyl and the like.

"C ₂ -C ₆ -alkynyl heteroaryl" refers to a C ₂ -C ₆ -alkynyl group having a heteroaryl substituent including 2-thienylethynyl and the like.

"C ₃ -C ₈ -cycloalkyl" refers to a saturated carbon ring having 3 to 8 carbon atoms having a single ring (eg cyclohexyl) or a polycondensed ring (eg norbornyl). Preferred cycloalkyls include cyclopentyl, cyclohexyl, norbornyl and the like.

"Heterocycloalkyl" refers to a C ₃ -C ₈ -cycloalkyl group according to the above definition, wherein up to three carbon atoms are substituted with heteroatoms selected from the group consisting of O, S, NR, and R is hydrogen or methyl Is defined as Preferred heterocycloalkyls include pyrrolidine, piperidine, piperazine, 1-methylpiperazine, morpholine and the like.

“C ₁ -C ₆ -alkyl Cycloalkyl” refers to a C ₁ -C ₆ -alkyl group having cycloalkyl substituents including cyclohexylmethyl, cyclopentylpropyl, and the like.

"C ₁ -C ₆ -alkyl heterocycloalkyl" is a hetero, including 2- (1-pyrrolidinyl) ethyl, 4-morpholinylmethyl, (1-methyl-4-piperidinyl) methyl and the like C ₁ -C ₆ -alkyl group having a cycloalkyl substituent.

"Carboxy" represents a -C (O) OH group.

"C ₁ -C ₆ -alkyl carboxy" refers to a C ₁ -C ₆ -alkyl group having carboxy substituents including 2-carboxyethyl and the like.

"Acyl" refers to the group -C (O) R, wherein R is "C ₁ -C ₆ -alkyl", "aryl", "heteroaryl", "C ₁ -C ₆ -alkyl aryl" or " C ₁ -C ₆ -alkyl heteroaryl ”.

"C ₁ -C ₆ -alkyl acyl" refers to a C ₁ -C ₆ -alkyl group having an acyl substituent including 2-acetylethyl and the like.

"Aryl acyl" refers to an aryl group having an acyl substituent, including 2-acetylphenyl and the like.

"Heteroaryl acyl" refers to a heteroaryl group having an acyl substituent, including 2-acetylpyridyl and the like.

"C ₃ -C _8- (hetero) cycloalkyl acyl" refers to a _3-8 membered cycloalkyl or heterocycloalkyl group having an acyl substituent.

"Acyloxy" refers to the group -OC (O) R, wherein R represents "C ₁ -C ₆ -alkyl", "C ₂ -C ₆ -alkenyl", "C ₂ -C ₆ -alkynyl "," C ₃ -C ₈ -cycloalkyl "," heterocycloalkyl "," aryl "," heteroaryl "," C ₁ -C ₆ -alkyl aryl "or" C ₁ -C ₆ -alkyl heteroaryl " , "C ₂ -C ₆ - alkenyl aryl", "C ₂ -C ₆ - alkenyl heteroaryl", "C ₂ -C ₆ - alkynyl aryl", "C ₂ -C ₆ - alkynyl heteroaryl" , “C ₁ -C ₆ -alkyl cycloalkyl”, “C ₁ -C ₆ -alkyl heterocycloalkyl”.

"C ₁ -C ₆ -alkyl acyloxy" refers to a C ₁ -C ₆ -alkyl group having an acyloxy substituent including 2- (acetyloxy) ethyl and the like.

"Alkoxy" refers to the group -OR, where R is "C ₁ -C ₆ -alkyl", or "aryl", or "heteroaryl", or "C ₁ -C ₆ -alkyl aryl" or "C ₁ -C ₆ -alkyl heteroaryl ". Preferred alkoxy groups include, for example, methoxy, ethoxy, phenoxy and the like.

"C ₁ -C ₆ -alkyl alkoxy" refers to a C ₁ -C ₆ -alkyl group having an alkoxy substituent, including 2-ethoxyethyl and the like.

"Alkoxycarbonyl" refers to a -C (O) OR group, where R is H, "C ₁ -C ₆ -alkyl", or "aryl", or "heteroaryl", or "C ₁ -C ₆ -alkyl aryl "or" C ₁ -C ₆ -alkyl heteroaryl ".

"C ₁ -C ₆ -alkyl alkoxycarbonyl" refers to a C ₁ -C ₅ -alkyl group having an alkoxycarbonyl substituent including 3- (benzyloxycarbonyl) ethyl and the like.

"Aminocarbonyl" refers to the group -C (O) NRR ', wherein R and R' are each independently hydrogen or C ₁ -C ₆ -alkyl, or aryl, or heteroaryl, or "C _1- C ₆ -alkyl aryl "or" C ₁ -C ₆ -alkyl heteroaryl ".

"C ₁ -C ₆ -alkyl aminocarbonyl" refers to a C ₁ -C ₆ -alkyl group having aminocarbonyl substituents including 2- (dimethylaminocarbonyl) ethyl and the like.

"Acylamino" refers to the group -NR (CO) R 'wherein R and R' are each independently hydrogen or "C ₁ -C ₆ -alkyl", "C ₂ -C ₆ -alkenyl", "C ₂ -C ₆ -alkynyl", "C ₃ -C ₈ -cycloalkyl", "heterocycloalkyl", "aryl", "heteroaryl", "C ₁ -C ₆ -alkyl aryl" or "C ₁ -C ₆ - alkyl heteroaryl "," C ₂ -C ₆ - alkenyl aryl "," C ₂ -C ₆ - alkenyl heteroaryl "," C ₂ -C ₆ - alkynyl aryl "," C ₂ -C ₆ -alkynylheteroaryl "," C ₁ -C ₆ -alkyl cycloalkyl "," C ₁ -C ₆ -alkyl heterocycloalkyl ".

"C ₁ -C ₆ -alkyl acylamino" refers to a C ₁ -C ₆ -alkyl group having an acylamino substituent including 2- (propionylamino) ethyl and the like.

"Ureido" refers to the group -NRC (O) NR'R ", wherein R, R 'and R" are each independently hydrogen, "C ₁ -C ₆ -alkyl", "C ₂ -C ₆ -Alkenyl "," C ₂ -C ₆ -alkynyl "," C ₃ -C ₈ -cycloalkyl "," heterocycloalkyl "," aryl "," heteroaryl "," C ₁ -C ₆ -alkyl aryl "or" C ₁ -C ₆ - alkyl heteroaryl "," C ₂ -C ₆ - alkenyl aryl "," C ₂ -C ₆ - alkenyl heteroaryl "," C ₂ -C ₆ - alkynyl, aryl "," C ₂ -C ₆ -alkynylheteroaryl "," C ₁ -C ₆ -alkyl cycloalkyl "," C ₁ -C ₆ -alkyl heterocycloalkyl ", wherein R 'and R" are nitrogen atoms And optionally a 3-8-membered heterocycloalkyl ring.

“C ₁ -C ₆ -alkyl ureido” refers to a C ₁ -C ₆ -alkyl group having ureido substituents including 2- (N-methylureido) ethyl and the like.

"Carbamate" refers to the group -NRC (O) OR 'wherein R and R' are each independently hydrogen, "C ₁ -C ₆ -alkyl", "C ₂ -C ₆ -alkenyl", "C ₂ -C ₆ -alkynyl", "C ₃ -C ₈ -cycloalkyl", "heterocycloalkyl", "aryl", "heteroaryl", "C ₁ -C ₆ -alkyl aryl" or " C ₁ -C ₆ - alkyl heteroaryl "," C ₂ -C ₆ - alkenyl aryl "," C ₂ -C ₆ - alkenyl heteroaryl "," C ₂ -C ₆ - alkynyl aryl "," C ₂ -C ₆ -alkynylheteroaryl "," C ₁ -C ₆ -alkyl cycloalkyl "," C ₁ -C ₆ -alkyl heterocycloalkyl ".

"Amino" is a -NRR 'group, wherein R, R' are each independently hydrogen or "C ₁ -C ₆ -alkyl" or "aryl" or "heteroaryl" or "C ₁ -C ₆ -alkyl aryl" Or “C ₁ -C ₆ -alkyl heteroaryl”, “cycloalkyl”, “heterocycloalkyl” wherein R and R ′ together with the nitrogen atom may optionally form a 3-8-membered heterocycloalkyl ring. have.

"C ₁ -C ₆ -alkyl amino" refers to a C ₁ -C ₅ -alkyl group having amino substituents including 2- (1-pyrrolidinyl) ethyl and the like.

"Ammonium" refers to -N ⁺ RR'R "positive charge, wherein R, R ', R" are each independently "C ₁ -C ₆ -alkyl", "C ₁ -C ₈ -alkyl aryl", " C ₁ -C ₆ -alkyl heteroaryl ”,“ cycloalkyl ”,“ heterocycloalkyl ”wherein R and R ′ together with the nitrogen atom may optionally form a 3-8-membered heterocycloalkyl ring.

"C ₁ -C ₆ -alkyl ammonium" refers to a C ₁ -C ₆ -alkyl group having an ammonium substituent, including 2- (1-pyrrolidinyl) ethyl and the like.

"Halogen" refers to fluorine, chlorine, bromine and iodine atoms.                 

"Sulfonyloxy" refers to the group -OSO ₂ -R, wherein R is H, "C ₁ -C ₆ -alkyl", eg, "C ₁ substituted with halogen, such as -OSO ₂ -CF ₃ group -C ₆ -alkyl "," C ₂ -C ₆ -alkenyl "," C ₂ -C ₆ -alkynyl "," C ₃ -C ₈ -cycloalkyl "," heterocycloalkyl "," aryl ", "Heteroaryl", "C ₁ -C ₆ -alkyl aryl", "C ₁ -C ₆ -alkyl heteroaryl", "C ₂ -C ₆ -alkenyl aryl", "C ₂ -C ₆ -kenyl hetero Aryl "," C ₂ -C ₆ -alkynyl aryl "," C ₂ -C ₆ -alkynylheteroaryl "," C ₁ -C ₆ -alkyl cycloalkyl "," C ₁ -C ₆ -alkyl heterocyclo Alkyl ".

"C ₁ -C ₆ -alkyl sulfonyloxy" refers to a C ₁ -C ₅ -alkyl group having sulfonyloxy substituents including 2- (methylsulfonyloxy) ethyl and the like.

"Sulfonyl" refers to the group "-SO ₂ -R" and R represents a halogen such as H, "aryl", "heteroaryl", "C ₁ -C ₆ -alkyl", for example -OSO ₂ -CF ₃ group. "C ₁ -C ₆ -alkyl", "C ₂ -C ₆ -alkenyl", "C ₂ -C ₆ -alkynyl", "C ₃ -C ₈ -cycloalkyl", "heterocycloalkyl""," Aryl "," heteroaryl "," C ₁ -C ₆ -alkyl aryl "," C ₁ -C ₆ -alkyl heteroaryl "," C ₂ -C ₆ -alkenyl aryl "," C _2- C ₆ - alkenyl heteroaryl "," C ₂ -C ₆ - alkynyl aryl "," C ₂ -C ₆ - alkynyl heteroaryl "," C ₁ -C ₆ - alkyl-cycloalkyl "," C ₁ - C ₆ -alkyl heterocycloalkyl ".

"C ₁ -C ₆ -alkyl sulfonyl" refers to a C ₁ -C ₅ -alkyl group having sulfonyl substituents including 2- (methylsulfonyl) ethyl and the like.

"Sulfinyl" refers to the group -S (O) -R, where R is H, "C ₁ -C ₆ -alkyl", eg, "C ₁ substituted with halogen, such as -OSO-CF ₃ group. -C ₆ -alkyl "," C ₂ -C ₆ -alkenyl "," C ₂ -C ₆ -alkynyl "," C ₃ -C ₈ -cycloalkyl "," heterocycloalkyl "," aryl ", "Heteroaryl", "C ₁ -C ₆ -alkyl aryl", "C ₁ -C ₆ -alkyl heteroaryl", "C ₂ -C ₆ -alkenyl aryl", "C ₂ -C ₆ -alkenyl hetero Aryl "," C ₂ -C ₆ -alkynyl aryl "," C ₂ -C ₆ -alkynylheteroaryl "," C ₁ -C ₆ -alkyl cycloalkyl "," C ₁ -C ₆ -alkyl heterocyclo Alkyl ".

"C ₁ -C ₆ -alkyl sulfinyl" refers to a C ₁ -C ₅ -alkyl group having sulfinyl substituents including 2- (methylsulfinyl) ethyl and the like.

"Sulfanyl" refers to the group -SR, R is H, "C ₁ -C ₆ -alkyl", eg "C ₁ -C ₆ -alkyl" substituted with halogen, such as -SO-CF ₃ group , "C ₂ -C ₆ -alkenyl", "C ₂ -C ₆ -alkynyl", "C ₃ -C ₈ -cycloalkyl", "heterocycloalkyl", "aryl", "heteroaryl", " C ₁ -C ₆ -alkyl aryl "," C ₁ -C ₆ -alkyl heteroaryl "," C ₂ -C ₆ -alkenyl aryl "," C ₂ -C ₆ -alkenyl heteroaryl "," C ₂ -C ₆ -alkynyl aryl "," C ₂ -C ₆ -alkynylheteroaryl "," C ₁ -C ₆ -alkyl cycloalkyl "," C ₁ -C ₆ -alkyl heterocycloalkyl ". Preferred sulfanyl groups include methylsulfanyl, ethylsulfanyl and the like.

"C ₁ -C ₆ -alkyl sulfanyl" refers to a C ₁ -C ₅ -alkyl group having sulfanyl substituents including 2- (ethylsulfanyl) ethyl and the like.

"Sulfonylamino" refers to the group -NRSO ₂ -R 'wherein R and R' are each independently hydrogen, "C ₁ -C ₆ -alkyl", "C ₂ -C ₆ -alkenyl", "C ₂ -C ₆ -alkynyl "," C ₃ -C ₈ -cycloalkyl "," heterocycloalkyl "," aryl "," heteroaryl "," C ₁ -C ₆ -alkyl aryl "," C ₁ -C ₆ -alkyl heteroaryl "," C ₂ -C ₆ - alkenyl aryl "," C ₂ -C ₆ - alkenyl heteroaryl "," C ₂ -C ₆ - alkynyl aryl "," C ₂ -C ₆ -Alkynylheteroaryl "," C ₁ -C ₆ -alkyl cycloalkyl "," C ₁ -C ₆ -alkyl heterocycloalkyl ".

"C ₁ -C ₆ -alkyl sulfonylamino" refers to a C ₁ -C ₅ -alkyl group having sulfonylamino substituents including 2- (ethylsulfonylamino) ethyl and the like.

"Aminosulfonyl" refers to the group -SO ₂ -NRR ', wherein R and R' are each independently hydrogen, "C ₁ -C ₆ -alkyl", "C ₂ -C ₆ -alkenyl", "C ₂ -C ₆ -alkynyl "," C ₃ -C ₈ -cycloalkyl "," heterocycloalkyl "," aryl "," heteroaryl "," C ₁ -C ₆ -alkyl aryl "," C ₁ -C ₆ -alkyl heteroaryl "," C ₂ -C ₆ - alkenyl aryl "," C ₂ -C ₆ - alkenyl heteroaryl "," C ₂ -C ₆ - alkynyl aryl "," C ₂ -C ₆ -Alkynylheteroaryl "," C ₁ -C ₆ -alkyl cycloalkyl "," C ₁ -C ₆ -alkyl heterocycloalkyl ".

"C ₁ -C ₆ -alkyl aminosulfonyl" refers to a C ₁ -C ₅ -alkyl group having aminosulfonyl substituents including 2- (cyclohexylaminosulfonyl) ethyl and the like.

"Unsubstituted or unsubstituted": groups, such as "alkyl", "alkenyl", "alkynyl", "aryl" and "heteroaryl" groups, etc., unless defined by the definition of the individual substituents, are "C ₁ -C" ₆ -alkyl "," C ₂ -C ₆ -alkenyl "," C ₂ -C ₆ -alkynyl "," cycloalkyl "," heterocycloalkyl "," C ₁ -C ₆ -alkyl aryl "," C ₁ -C ₆ -alkyl heteroaryl ”,“ C ₁ -C ₆ -alkyl alkyl cycloalkyl ”,“ amino ”,“ ammonium ”,“ acyl ”,“ acyloxy ”,“ acylamino ”,“ aminocarbonyl "," Alkoxycarbonyl "," ureido "," aryl "," carbamate "," heteroaryl "," sulfinyl "," sulfonyl "," alkoxy "," sulfanyl "," halogen ", Optionally 1-5 substituents selected from the group consisting of "carboxy", trihalomethyl, cyano, hydroxy, mercapto, nitro, and the like. The substituents also form when the adjacent substituents form a ring, in particular when adjacent functional substituents are involved, for example lactam, lacton, cyclic anhydride, and also for example a protecting group Form acetals, thioacetals, aminals, etc., formed by ring formation to obtain.

“Pharmaceutically acceptable cationic salts or complexes” include alkali metal salts (eg sodium and potassium), alkaline earth metal salts (eg calcium or magnesium), aluminum salts, ammonium salts and Amines of the formula —NR, R ′, R ″ (where R, R ′, R ″ are independently hydrogen, alkyl or benzyl), as well as methylamine, dimethylamine, trimethylamine, ethylamine, triethylamine, morpholine , N-Me-D-glucamine, N, N'-bis (phenylmethyl) -1,2-ethanediamine, ethanolamine, diethanolamine, ethylenediamine, N-methylmorpholine, piperidine, benzatin (N, N'-dibenzylethylenediamine) [benzathine (N, N'-dibenzylethylenediamine)], choline, ethylene-diamine, meglumine (N-methylglucamine) [meglumine (N-methylglucamine)] Beethamine (N-benzylphenethylamine), diethylamine, piperazine, tromethamine (2-amino-2-hydroxy To define the salts such as organic amine salts such as methyl-1,3-propanediol), procaine (procaine). Particularly preferred salts are sodium and potassium salts.

“Pharmaceutically acceptable salts or complexes” refers to salts or complexes of the compounds specified below of the invention that possess the desired biological activity. Each salt is, for example, acid addition salts formed with inorganic acids (e.g. hydrochloric acid, bromic acid, sulfuric acid, phosphoric acid, nitric acid, etc.), as well as acetic acid, oxalic acid, tartaric acid and succinic acid ( succinic acid, malic aicd, fumaric acid, maleic acid, maleic acid, ascorbic acid, benzoic acid, tannic acid, pamoic acid, alginic acid Also included are salts formed by organic acids such as alginic acid, polyglutamic acid, naphthalene sulfonic acid, naphthalene disulfonic acid, and poly-galacturonic acid. Such compounds may also be provided as pharmaceutically acceptable quaternary salts known to those skilled in the art, including quaternary salts of the formula —NR, R ′, R ″ ⁺ , Z ⁻ , wherein R, R ′, Each R ″ is independently hydrogen, alkyl or benzyl, C ₁ -C ₆ -alkyl, C ₂ -C ₆ -alkenyl, C ₂ -C ₆ -alkynyl, C ₁ -C ₆ -alkyl aryl, C _1- C ₆ -alkyl heteroaryl, cycloalkyl, heterocycloalkyl, Z is a counterion, chlorine, bromine, iodine, —O-alkyl, toluenesulfonate, methylsulfonate, sulfonate, phosphate, or carboxyl Latex [benzoate, succinate, acetate, glycolate, maleate, malate, fumarate, citrate, tartrate, ascorbate, Such as cinnamoate, mandeloate and diphenyl acetate]; .

A “pharmaceutically active derivative” refers to any compound that can provide, directly or indirectly, the activity described herein when administered to a receptor.

"Enantiomeric excess (ee)" refers to a compound obtained by asymmetric synthesis, ie synthesis involving non-racemic starting materials and / or reagents or synthesis comprising at least one enantioselective step. This results in an extra one optical isomer of at least about 52% ee.

Formula (I) according to the present invention also provides for its tautomer, its geometric isomers, diastereomers, optically active forms, and racemic forms thereof. As well as pharmaceutically acceptable salts thereof. Preferred pharmaceutically acceptable salts of the formulas of the present invention are hydrochloride, bromate, sulfate, bisulfate, phosphate or hydrogen sulfate, acetate, benzoate, succinate, fumarate, maleate, lactate, citrate Also included are acid addition salts formed with pharmaceutically acceptable acids such as tartarate, gluconate, methanesulfonate, benzenesulfonate, para- toluenesulfonate.

The compounds of the present invention can be obtained as E / Z isomer mixtures or as pure E-isomers or as pure Z-isomers. E / Z isomerism preferably represents a vinyl moiety connecting the azolidinone moiety and phenyl. As a specific example, the compounds of formula (I) are Z-isomers.

The first aspect of the present invention is directed to autoimmune and / or inflammatory diseases, cardiovascular disease, neurodegenerative diseases, bacterial or viral infections, kidney disease, platelet aggregation, cancer, transplant complications due to rejection, graft rejection or lung injury. Optically active forms such as the compounds of formula (I), their geometric isomers, diastereoisomers, enantiomers, and racemic forms thereof, pharmaceutically acceptable for preparing prophylactic and / or therapeutic drugs Salts and pharmaceutically active derivatives thereof.

(I)

(I)

In a preferred embodiment, these compounds are multiple sclerosis, psoriasis, rheumatoid arthritis, systemic lupus erythematosis, inflammatory bowel disease, lung inflammation It is useful for the treatment and / or prophylaxis of autoimmune diseases or inflammatory diseases such as inflammation, thrombosis or brain infection / inflammation such as meningitis or encephalitis.

In another preferred embodiment according to the present invention, these compounds are polysclerosis, Alzheimer's disease, Huntington's disease, CNS trauma, stroke or ischemic condition. It is useful for the treatment and / or prevention of degenerative neurological diseases, including.

In a particularly preferred embodiment of the present invention, these compounds may be used for atherosclerosis, heart hypertrophy, cardiac myocyte dysfunction, elevated blood pressure or vasoconstriction. It is useful for the treatment and / or prevention of cardiovascular diseases such as.

In another particularly preferred embodiment according to the present invention, these compounds are rejected, graft rejection, glomerulo sclerosis, glomerulo nephritis, progressive renal fibrosis, lung or general lung airway inflammation Chronic obstructive pulmonary disease, anaphylactic shock fibrosis, psoriasis, allergic diseases, asthma, stroke or ischemic disease, ischemia-isperfusion due to endothelial and epithelial damage reperfusion, platelet aggregation / activation, skeletal muscle atrophy / hypertrophy, leukocyte recruitment in cancer tissue, angiogenesis, invasion metastisis, especially melanin Melanoma, Karposi's sarcoma, acute and chronic bacterial and viral infections, sepsis, transplantation It is useful for the treatment and / or prevention.

Substituents of formula (I) are defined as follows:

A is a substituted or unsubstituted 5-8-membered heterocyclic group or an unsubstituted or substituted carbocyclic group.

The carbocycle group can be conjugated with substituted or unsubstituted aryl, unsubstituted or substituted heteroaryl, unsubstituted or substituted cycloalkyl or unsubstituted heterocycloalkyl.

Such heterocycle groups or carbocycle groups are phenyl, phenathrenyl, cyclopentyl, cyclohexyl, norbornyl, pyrrolidine, piperidine, piperazine, 1-methylpiperazine, morpholin, pyrrolyl, furanyl, Thienyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,3-oxa Diazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, 1,3,4-triazinyl, 1,2,3-triazinyl , Benzofuryl, [2,3-dihydro] benzofuryl, isobenzofuryl, benzothienyl, benzotriazolyl, isobenzothienyl, indolyl, isoindoleyl, 3H-indolyl, benzimidazolyl, imi Dazo [1,2-a] pyridyl, benzothiazolyl, benzoxazolyl, quinolinzyl, quinazolinyl, phthalazinyl, quinoxalinyl, cinnolinyl, naphthyridinyl, pyrido [3,4- b] pyridyl, pyrido [3,2-b] pyridyl, pyrido [4,3-b] pyridyl, quine Nolyl, isoquinolyl, tetrazolyl, 5,6,7,8-tetrahydroquinolyl, 5,6,7,8-tetrahydroisoquinolyl, purinyl, pteridinyl, carba Aryl, heteroaryl, cycloalkyl and heterocycloalkyl including zolyl, xanthenyl or benzoquinolyl.

Another exemplary heterocycle or carbocycle group A is unsubstituted or substituted dioxol, unsubstituted or substituted dioxin, unsubstituted or substituted dihydrofuran, unsubstituted or substituted (Dihydro) furanyl, unsubstituted or substituted (dihydro) oxazinyl, unsubstituted or substituted oxazinoyl, unsubstituted or substituted pyridinyl, unsubstituted or substituted isoxazolyl, unsubstituted or substituted Oxazolyl, unsubstituted or substituted (dihydro) naphthalenyl, unsubstituted or substituted pyrimidinyl, unsubstituted or substituted triazolyl, unsubstituted or substituted imidazolyl, unsubstituted or substituted pyrazinyl, Unsubstituted or substituted thiazolyl, unsubstituted or substituted thiadiazolyl, unsubstituted or substituted oxdiazolyl.

X is S, O or NH, preferably S.

Y ¹ and Y ² are independently selected from the group consisting of S, O, or -NH, and are preferably O.

Z is S or O, preferably O.

R ¹ is H, CN, carboxy, acyl, C ₁ -C ₆ -alkoxy, halogen, hydroxy, acyloxy, unsubstituted or substituted C ₁ -C ₆ -alkyl carboxy, substituted or unsubstituted C ₁ -C ₆ -alkyl acyloxy, unsubstituted or substituted C ₁ -C ₆ -alkyl alkoxy, alkoxycarbonyl, unsubstituted or substituted C ₁ -C ₆ -alkyl alkoxycarbonyl, aminocarbonyl, unsubstituted or substituted C _1- C ₆ -alkyl aminocarbonyl, acylamino, unsubstituted or substituted C ₁ -C ₆ -alkyl acylamino, ureido, unsubstituted or substituted C ₁ -C ₆ -alkyl ureido, amino, unsubstituted or substituted C ₁ -C ₆ - alkylamino, ammonium, sulfonyl, hydroxy, unsubstituted or chihoen a C ₁ -C ₆ - alkylsulfonyl, hydroxy, sulfonyl, substituted or unsubstituted C ₁ -C ₆ - alkylsulfonyl sulfonyl, sulfinyl, substituted or unsubstituted C ₁ -C ₆ - alkyl sulfinyl, sulfanyl, being optionally substituted Are C ₁ -C ₆ - alkyl, sulfanyl, sulfonyl, amino, unsubstituted or substituted C ₁ -C ₆ - or made of alkylsulfonylamino or carbamate is selected from the group comprising the same. In a specific embodiment R ¹ is H.

R ² is H, halogen, acyl, amino, unsubstituted or substituted C ₁ -C ₆ -alkyl, unsubstituted or substituted C ₂ -C ₆ -alkenyl, unsubstituted or substituted C ₂ -C ₆ -alky Unsubstituted or substituted C ₁ -C ₆ -alkyl carboxy, unsubstituted or substituted C ₁ -C ₆ -alkyl acyl, unsubstituted or substituted C ₁ -C ₆ -alkyl alkoxycarbonyl, unsubstituted or substituted C ₁ -C ₆ -alkyl aminocarbonyl, unsubstituted or substituted C ₁ -C ₆ -alkyl acyloxy, unsubstituted or substituted C ₁ -C ₆ -alkyl acylamino, unsubstituted or substituted C _1- C ₆ -alkyl ureido, unsubstituted or substituted C ₁ -C ₆ -alkyl carbamate, unsubstituted or substituted C ₁ -C ₆ -alkyl amino, unsubstituted or substituted C ₁ -C ₆ -alkyl alkoxy, an unsubstituted or substituted C ₁ -C ₆ - alkyl sulfanyl, unsubstituted or substituted C ₁ -C ₆ - alkylsulfinyl, is optionally substituted with value A C ₁ -C ₆ - alkylsulfonyl, unsubstituted or substituted C ₁ -C ₆ - alkylsulfonylamino aryl, unsubstituted or substituted aryl, unsubstituted or substituted C ₃ -C ₈ - cycloalkyl or heteroaryl Cycloalkyl, unsubstituted or substituted C ₁ -C ₆ -alkyl aryl, unsubstituted or substituted C ₂ -C ₆ -alkenyl-aryl, unsubstituted or substituted C ₂ -C ₆ -alkynyl aryl, carboxy, Selected from the group consisting of or comprising cyano, hydroxy, C ₁ -C ₆ -alkoxy, nitro, acylamino, ureido, sulfonylamino, sulfanyl, or sulfonyl.

n is an integer 0, 1 or 2, Preferably n is 0 or 1. Most preferably n = 0.

According to an embodiment of the invention, both R ¹ and R ² are H.

In an embodiment according to the invention, X is S, Y ¹ and Y ² are all O, R ¹ and R ² are as defined above and n is 0.

Particularly preferred embodiments of the invention include autoimmune diseases and / or inflammatory diseases, cardiovascular diseases, neurodegenerative diseases, bacterial or viral infections, kidney disease, platelet aggregation, cancer, transplant complications due to rejection reactions, graft rejection or lung injury. Use of thiazolidinedione-vinyl fused-benzene derivatives of formulas (Ia), (Ib), (Ic) and (Id) for the preparation of drugs for the prophylaxis and / or treatment of It is about:

(Ia)

(Ia)

R ¹ , R ² , Y ¹ , Z and n in Formula (Ia) are as defined above.

G in formula (Ia) is an unsubstituted or substituted C ₁ -C ₅ -alkylene (eg methylene, ethylene, propylene, etc.) or an unsubstituted or substituted C ₁ -C ₅ -alkenylene group (eg Methine (-CH =), -CH = CH- group, propenylene group and the like).

W and V in formula (Ia) are each independently selected from O, S, -NR ³ , wherein R ³ is H or an unsubstituted or substituted C ₁ -C ₆ -alkyl group, m and o are each independently 0 or 1; o is an integer 1-4 and q is an integer 0-4.

More preferred compounds of formula (Ia) are those wherein G is C ₁ -C ₄ alkylene, giving compounds of formula (Ib) (eg p = 1, 2, 3 or 4, preferably 1 or 2) do.

(Ib)

(Ib)

Specific sub-groups of formula (Ib) are compounds having formula (Ic), wherein W, R ¹ , Y ¹ are as described above; Specifically R ¹ is an unsubstituted or substituted C ₁ -C ₄ alkyl group or an unsubstituted or substituted C ₁ -C ₅ alkenyl group, carboxy, cyano, C ₁ -C ₄ alkoxy, nitro, acylamino, ureidoyl Can be.

(Ic)

(Ic)

Even more specific subgroups of formula (Ia) are compounds in which V, W and Y ¹ are all O to provide compounds of formula (Id).

(Id)

(Id)

In a preferred embodiment of formula (Ia), (Ib) or (Id) n is 0, m is 1, p is 1 or 2, o is 0, q is 1 and R ¹ and R ² are as defined above. same.

In specific embodiments of Formula (Ia), (Ib) or (Id), m is 1, n is 0, p is 1 or 2, q is 0, o is 1 and R ¹ and R ² are defined above In more detail, R ¹ is a halogen or a hydrogen atom.

In more specific embodiments of Formula (Ia), (Ib) or (Id), p is 1 or 2, q is 0, m is 0, n is 1 and R ¹ and R ² are as defined above. In more detail, R ¹ is a halogen or a hydrogen atom.

The compounds of the present invention are suitable for modulation, in particular for the inhibition of phosphatoinositide 3-kinase (PI3K), in particular phosphatoinositide 3-kinase (PI3Kγ) activity. The compounds of the present invention are therefore believed to be particularly useful for the treatment and / or prevention of diseases regulated by PI3K, in particular PI3Kγ. The treatment is related to regulation—especially inhibition or down-regulation of phosphatoinositide 3-kinase.

The following compounds are not included by formula (I):

R ¹ is lower alkyl or aralkyl and R ² is H or halogen. Compound TE is disclosed as intermediate compound without any biological activity in Japanese Patent No. 55 045648, while JA is a paw swelling assay in Journal of Medicinal Chemistry (1998), 41 (18), 3515-3529. Inactive).

Compounds of the invention particularly include compounds of the group consisting of:

5- (1,3-benzodioxol-5-ylmethylene) -1,3-thiazolidine-2,4-dione

5- (1,3-benzodioxol-5-ylmethylene) -2-thioxo-1,3-thiazolidin-4-one

5- (2,3-dihydro-1,4-benzodioxin-6-ylmethylene) -1,3-thiazolidine-2,4-dione

5- (2,3-dihydro-1-benzofuran-5-ylmethylene) -1,3-thiazolidine-2,4-dione

5-[(7-methoxy-1,3-benzodioxol-5-yl) methylene] -1,3-thiazolidine-2,4-dione

5-[(9,10-dioxo-9,10-dihydroanthracen-2-yl) methylene] -1,3-thiazolidine-2,4-dione

(5-[(2,2-difluoro-1,3-benzodioxol-5-yl) methylene] -1,3-thiazolidine-2,4-dione

(5Z) -5- (1,3-dihydro-2-benzofuran-5-ylmethylene) -1,3-thiazolidine-2,4-dione

5- (1-benzofuran-5-ylmethylene) -1,3-thiazolidine-2,4-dione

5-[(4-methyl-3-oxo-dihydro-2H-1,4-benzoxazin-6-yl) methylene] -1,3-thiazolidine-2,4-dione

5- (1,3-benzodioxol-5-ylmethylene) -2-imino-1,3-thiazolidin-4-one

5-quinolin-6-ylmethylene-thiazolidine-2,4-dione

5-quinolin-6-ylmethylene-2-thioxo-thiazolidin-4-one

2-imino-5-quinolin-6-ylmethylene-thiazolidin-4-one

5- (3-Methyl-benzo [d] isoxazol-5-ylmethylene) -thiazolidine-2,4-dione                 

5- (4-phenyl-quinazolin-6-ylmethylene) -thiazolidine-2,4-dione

5- (4-Dimethylamino-quinazolin-6-ylmethylene) -thiazolidine-2,4-dione

5-[(4-aminoquinazolin-6-yl) methylene] -1,3-thiazolidine-2,4-dione

5-[(4-piperidin-1-ylquinazolin-6-yl) methylene] -1,3-thiazolidine-2,4-dione

5-[(4-morpholin-4-ylquinazolin-6-yl) methylene] -1,3-thiazolidine-2,4-dione

5-{[4- (benzylamino) quinazolin-6-yl] methylene} -1,3-thiazolidine-2,4-dione

5-{[4- (diethylamino) quinazolin-6-yl] methylene} -1,3-thiazolidine-2,4-dione

5-({4-[(pyridin-2-ylmethyl) amino] quinazolin-6-yl} methylene) -1,3-thiazolidine-2,4-dione

5-({4-[(pyridin-3-ylmethyl) amino] quinazolin-6-yl} methylene-1,3-thiazolidine-2,4-dione

Ethyl 1- {6-[(2,4-dioxo-1,3-thiazolidine-5-ylidene) methyl] quinazolin-4-yl} piperidine-3-carboxylate

Ethyl 1- {6-[(2,4-dioxo-1,3-thiazolidine-5-ylidene) methyl] quinazolin-4-yl} piperidine-4-carboxylate

tert-butyl 1- {6-[(2,4-dioxo-1,3-quinazolin-5-ylidene) methyl] quinazolin-4-yl} -L-prolinate

5-{[4- (4-methylpiperazin-1-yl) quinazolin-6-yl] methylene} -1,3-thiazolidine-2,4-dione

5-{[4- (4-pyrimidin-2-ylpiperazin-1-yl) quinazolin-6-yl] methylene} -1,3-thiazolidine-2,4-dione

5-({4- [4- (4-fluorophenyl) piperidin-1-yl] quinazolin-6-yl} methylene) -1,3-thiazolidine-2,4-dione

5-{[4- (4-benzylpiperidin-1-yl) quinazolin-6-yl] methylene} -1,3-thiazolidine-2,4-dione

5 ({4- [4- (2-phenylethyl) piperidin-1-yl] quinazolin-6-yl} methylene) -1,3-thiazolidine-2,4-dione

5-{[4- (4-methylpiperidin-1-yl) quinazolin-6-yl] methylene} -1,3-thiazolidine-2,4-dione

5-{[4- (4-hydroxypiperidin-1-yl) quinazolin-6-yl] methylene} -1,3-thiazolidine-2,4-dione

1- [6- (2,4-Dioxo-thiazolidine-5-ylidenemethyl-quinazolin-4-yl] -piperidine-4-carboxylic acid

1- [6- (2,4-Dioxo-thiazolidine-5-ylidenemethyl) -quinazolin-4-yl] -piperidine-3-carboxylic acid

1- [6- (2,4-Dioxo-thiazolidine-5-ylidenemethyl) -quinazolin-4-yl] -pyrrolidine-2-carbosylic acid

5- (4-Methylamino-quinazolin-6-ylmethylene) -thiazolidine-2,4-dione

5- (4-methoxy-quinazolin-6-ylmethylene) -thiazolidine-2,4-dione

2-imino-5- (4-methylamino-quinazolin-6-ylmethylene) -thiazolidin-4-one                 

2-imino-5- (4-piperidin-quinazolin-6-ylmethylene) -thiazolidin-4-one

2-imino-5- (4-dimethylamino-quinazolin-6-ylmethylene) -thiazolidin-4-one

5- (2-Methyl-2H-benzotriazol-5-ylmethylene) -thiazolidine-2,4-dione

5- (3-Methyl-3H-benzotriazol-5-ylmethylene) -thiazolidine-2,4-dione

5- (3-ethyl-3H-benzoimidazol-5-ylmethylene) -thiazolidine-2,4-dione

5-{[1- (4-phenylbutyl) -1H-benzimidazol-6-yl] methylene} -1,3-thiazolidine-2,4-dione

5-[(1-prop-2-yn-1-yl-1H-benzimidazol-6-yl) methylene] -1,3-thiazolidine-2,4-dione

5-[(1- {2- [4- (trifluoromethyl) phenyl] ethyl} -1H-benzimidazol-6-yl) methylene] -1,3-thiazolidine-2,4-dione

5-({1- [2- (4-hydroxyphenyl) ethyl] -1H-benzimidazol-6-yl} methylene) -1,3-thiazolidine-2,4-dione

Methyl 4- {6-[(2,4-dioxo-1,3-thiazolidine-5-ylidene) methyl] -1H-benzimidazol-1-yl} cyclohexanecarboxylate

5-({1- [2- (5-methoxy-1H-indol-3-yl) ethyl] -1H-benzimidazol-6-yl} methylene) -1,3-thiazolidine-2,4 Dion

5-({1-[(1-methyl-1H-pyrazol-4-yl) methyl] -1H-benzimidazol-6-yl} methylene) -1,3-thiazolidine-2,4-dione

5-({1- [2- (3,4-dimethoxyfetyl) ethyl] -1H-benzimidazol-6-yl} methylene) -1,3-thiazolidine-2,4-dione                 

5-({1- [2- (4-phenoxyphenyl) ethyl] -1H-benzimidazol-6-yl} methylene) -1,3-thiazolidine-2,4-dione

5-({1- [4- (trifluoromethyl) benzyl] -H-benzimidazol-6-yl} methylene) -1,3-thiazolidine-2,4-dione

4- {6-[(2,4-dioxo-1,3-thiazolidine-5-ylidene) methyl] -1H-benzimidazol-1-yl} cyclohexanecarboxylic acid

5-[(1-isobutyl-1H-benzimidazol-6-yl) methylene] -1,3-thiazolidine-2,4-dione

5-({1- [2- (1,3-benzodioxol-4-yl) ethyl] -1H-benzimidazol-6-yl} methylene) -1,3-thiazolidine-2,4- Dion

5-({1- [2- (2-phenoxyphenyl) ethyl] -1H-benzimidazol-6-yl} methylene) -1,3-thiazolidine-2,4-dione

5-{[1- (3,3-diphenylpropyl) -1H-benzimidazol-6-yl] methylene} -1,3-thiazolidine-2,4-dione

5-{[1- (2-methoxybenzyl) -1H-benzimidazol-6-yl] methylene} -1,3-thiazolidine-2,4-dione

5-{[1- (3-furylmethyl) -1H-benzimidazol-6-yl] methylene} -1,3-thiazolidine-2,4-dione

5-[(1-propyl-1H-benzimidazol-6-yl] methylene} -1,3-thiazolidine-2,4-dione

5-quinoxaline-6-ylmethylene-thiazolidine-2,4-dione

5-quinoxalin-6-ylmethylene-2-thioxo-thiazolidin-4-one

2-imino-5-quinoxalin-6-ylmethylene-thiazolidin-4-one                 

5-benzothiazol-6-ylmethylene-thiazolidine-2,4-dione

5- (3-Methyl-benzofuran-5-ylmethylene) -thiazolidine-2,4-dione

5- (2-Bromo-3-methyl-benzofuran-5-ylmethylene) -thiazolidine-2,4-dione

5- (3-Bromo-benzofuran-5-ylmethylene) -thiazolidine-2,4-dione

3- [5- (2,4-Dioxo-thiazolidine-5-ylidenemethyl) -benzofuran-3-yl] -acrylic acid ethyl ester

3- [5- (2,4-Dioxo-thiazolidine-5-ylidenemethyl) -benzofuran-3-yl] -acrylic acid

5- [3- (3-Oxo-3-piperidin-1-yl-propenyl) -benzofuran-5-ylmethylene] -thiazolidine-2,4-dione

Methyl 1-((3- {5-[(2,4-dioxo-1,3-thiazolidin-5-ylidene) methyl] -1-benzofuran-3-yl} prop-2-ene Oil) prolinate

Methyl 1-((3- {5-[(2,4-dioxo-1,3-thiazolidin-5-ylidene) methyl] -1-benzofuran-3-yl} prop-2-ene Oil) -D-prolinate

(5-({3-[(3-oxo-3-pyrrolidin-1-ylprop-1-en-1-yl] -1-benzofuran-5-yl} methylene) -1,3- Thiazolidine-2,4-dione

5-({3- [3-morpholin-4-yl-3-oxoprop-1-en-1-yl] -1-benzofuran-5-yl} methylene) -1,3-thiazolidine -2,4-dione

Methyl 1- (3- {5-[(2,4-dioxo-1,3-thiazolidin-5-ylidene) methyl] -1-benzofuran-3-yl} prop-2-enoyl ) -L-prolinate

N-cyclohexyl-3- {5-[(2,4-dioxo-1,3-thiazolidin-5-ylidene) methyl] -1-benzofuran-3-yl} -N-methylacrylic amides

3- {5-[(2,4-dioxo-1,3-thiazolidine-5-ylidene) methyl] -1-benzofuran-3-yl} -N-ethyl-N- (2-hydr Oxyethyl) acrylamide

N-cyclobutyl-3- {5-[(2,4-dioxo-1,3-thiazolidin-5-ylidene) methyl] -1-benzofuran-3-yl} acrylamide

5-({3- [3-azetidin-1-yl-3-oxoprop-1-en-1-yl] -1-benzofuran-5-yl} methylene) -1,3-thiazolidine -2,4-dione

5-({3- [3- (1,3-Dihydro-2H-isoindol-2-yl) -3-oxoprop-1-en-1-yl] -1-benzofuran-5-yl Methylene) -1,3-thiazolidine-2,4-dione

5-({3- [3-Azepan-1-yl-3-oxoprop-1-en-1-yl] -1-benzofuran-5-yl} methylene-1,3-thiazolidine- 2,4-dione

3- {5-[(2,4-dioxo-1,3-thiazolidine-5-ylidene) methyl] -1-benzofuran-3-yl} -N-piperidin-1-ylacrylic amides

3- {5-[(2,4-dioxo-1,3-thiazolidine-5-ylidene) methyl] -1-benzofuran-3-yl} -N- (pyridin-3-ylmethyl) Acrylamide

N-cyclohexyl-3- {5-[(2,4-dioxo-1,3-thiazolidin-5-ylidene) methyl] -1-benzofuran-3-yl} acrylamide

5-({3- [3- (4-methylpiperazin-1-yl) -3-oxoprop-1-en-1-yl] -1-benzofuran-5-yl} methylene) -1, 3-thiazolidine-2,4-dione

N-cycloheptyl-3- {5-[(2,4-dioxo-1,3-thiazolidine-5-ylidene) methyl] -1-benzofuran-3-yl} acrylamide

5-({3- [3- (2,5-Dihydro-1H-pyrrol-1-yl) -3-oxoprop-1-en-1-yl] -1-benzofuran-5-yl} Methylene) -1,3-thiazolidine-2,4-dione

N-cyclopentyl-3- {5-[(2,4-dioxo-1,3-thiazolidin-5-ylidene) methyl] -1-benzofuran-3-yl} acrylamide

3- [5- (2,4-Dioxo-thiazolidine-5-ylidenemethyl) -benzofuran-3-yl] -propionic acid ethyl ester

3- [5- (2,4-Dioxo-thiazolidine-5-ylidenemethyl) -benzofuran-3-yl] -propionic acid

5- [3- (3-Oxo-3-piperidin-1-yl-propyl) -benzofuran-5-ylmethylene] -thiazolidine-2,4-dione

6- (2,4-dioxo-thiazolidine-5-ylidenemethyl) -2,3-dihydro-benzo [1,4] oxazine-4-carboxylic acid tert-butyl ester

5- (3,4-Dihydro-2H-benzo [1,4] oxazin-6-ylmethylene) -thiazolidine-2,4-dione

5- (4-benzoyl-3,4-dihydro-2H-benzo [1,4] oxazin-6-ylmethylene) -thiazolidine-2,4-dione

5- (4-acetyl-3,4-dihydro-2H-benzo [1,4] oxazin-6-ylmethylene) -thiazolidine-2,4-dione

6- (2,4-dioxo-thiazolidine-5-ylidenemethyl) -benzo [1,4] oxazine-4-carboxylic acid tert-butyl ester

[6- (2,4-Dioxo-thiazolidine-5-ylidenemethyl) -3-oxo-2,3-dihydro-benzo [1,4] -oxazin-4-yl] -methyl acetate ester

N-benzyl-2- [6- (2,4-dioxo-thiazolidine-5-ylidenemethyl) -3-oxo-2,3-dihydro-benzo [1,4] oxazine-4- General] -acetamide

5- (4-Butyl-3-oxo-3,4-dihydro-2H-benzo [1,4] oxazin-6-ylmethylene) -thiazolidine-2,4-dione

5- (4-benzyl-3-oxo-3,4-dihydro-2H-benzo [1,4] oxazin-6-ylmethylene) -thiazolidine-2,4-dione

5- (2-Chloro-benzofuran-5-ylmethylene) -thiazolidine-2,4-dione

5- (3-Amino-benzo [d] isoxazol-5-ylmethylene) -thiazolidine-2,4-dione

5- (3-phenylethynyl-benzofuran-5-ylmethylene) -thiazolidine-2,4-dione

5-benzo [1,2,5] thiadiazol-5-ylmethylene-thiazolidine-2,4-dione

5-benzo [1,2,5] oxodiazol-5-ylmethylene-thiazolidine-2,4-dione

5- (2-Methyl-benzofuran-6-ylmethylene) -thiazolidine-2,4-dione

5- (2-carboxymethyl-benzofuran-6-ylmethylene) -thiazolidine-2,4-dione

5- (3-Bromo-2-fluoro-2,3-dihydro-benzofuran-6-ylmethylene) -thiazolidine-2,4-dione

5- (2-Fluoro-benzofuran-6-ylmethylene) -thiazolidine-2,4-dione

Another aspect of the invention consists of a novel thiazolidinedione-vinyl conjugated-benzene derivative of formula (II-a).

(II-a)

(II-a)

A is substituted or unsubstituted dioxol, unsubstituted or substituted dioxin, unsubstituted or substituted dihydrofuran, unsubstituted or substituted (dihydro) furanyl, unsubstituted or substituted (dihydro) oxazinyl Unsubstituted or substituted oxazinoyl, unsubstituted or substituted pyridinyl, unsubstituted or substituted isooxazolyl, unsubstituted or substituted oxazolyl, unsubstituted or substituted (dihydro) naphthalenyl, unsubstituted Unsubstituted or substituted pyrimidinyl, unsubstituted or substituted triazolyl, unsubstituted or substituted imidazolyl, unsubstituted or substituted pyrazinyl, unsubstituted or substituted thiazolyl, unsubstituted or substituted thiadiazolyl, substituted Unsubstituted or substituted oxadiazolyl.

R ² is H, halogen, acyl, amino, unsubstituted or substituted C ₁ -C ₆ -alkyl, unsubstituted or substituted C ₂ -C ₆ -alkenyl, unsubstituted or substituted C ₂ -C ₆ -alky Unsubstituted or substituted C ₁ -C ₆ -alkyl carboxy, unsubstituted or substituted C ₁ -C ₆ -alkyl acyl, unsubstituted or substituted C ₁ -C ₆ -alkyl alkoxycarbonyl, unsubstituted or substituted C ₁ -C ₆ -alkyl aminocarbonyl, unsubstituted or substituted C ₁ -C ₆ -alkyl acyloxy, unsubstituted or substituted C ₁ -C ₆ -alkyl acylamino, unsubstituted or substituted C _1- C ₆ -alkyl ureido, unsubstituted or substituted C ₁ -C ₆ -alkyl carbamate, unsubstituted or substituted C ₁ -C ₆ -alkyl amino, unsubstituted or substituted C ₁ -C ₆ -alkyl alkoxy, unsubstituted or substituted C ₁ -C ₆ - alkyl sulfanyl, unsubstituted or substituted C ₁ -C ₆ - alkylsulfinyl, is optionally substituted with Hwandoen C ₁ -C ₆ - alkylsulfonyl, unsubstituted or substituted C ₁ -C ₆ - alkylsulfonylamino aryl, unsubstituted or substituted aryl, unsubstituted or substituted C ₃ -C ₈ - cycloalkyl or heteroaryl Cycloalkyl, unsubstituted or substituted C ₁ -C ₆ -alkyl aryl, unsubstituted or substituted C ₂ -C ₆ -alkenyl-aryl, unsubstituted or substituted C ₂ -C ₆ -alkynyl aryl, carboxy, Cyano, hydroxy, C ₁ -C ₆ -alkoxy, nitro, acylamino, ureido, sulfonylamino, sulfanyl or sulfonyl or selected from the group consisting of these.

More specific new thiazolidinone-vinyl conjugated-benzene derivatives of formula (II), its optically active forms such as geometric isomers, enantiomers, diastereomers and racemic forms thereof, or medicaments thereof Pharmaceutically acceptable salts and pharmaceutically active derivatives wherein Y ¹ , Z, R ¹ , R ² are as defined above and n is 0 or 1.

(II)

(II)

In specific embodiments, R ¹ is unsubstituted or substituted C ₁ -C ₆ -alkyl, unsubstituted or substituted C ₁ -C ₆ -alkyl aryl, unsubstituted or substituted aryl, unsubstituted or substituted C ₁ -C ₆ -alkyl aryl, unsubstituted or substituted aryl, unsubstituted or substituted C ₃ -C ₈ -cycloalkyl or -heterocycloalkyl, unsubstituted or substituted C ₁ -C ₆ -alkyl aryl, unsubstituted or substituted C ₂ -C ₆ -alkenyl-aryl, unsubstituted or substituted C ₂ -C ₆ -alkynyl aryl.

In another preferred embodiment according to the invention Y ¹ is O.

Another aspect of the present invention is a novel thiazolidinone-vinyl conjugated-benzene derivative of formula (III), its optically active forms such as geometric isomers, enantiomers, diastereomers and racemic forms thereof, Or a pharmaceutically acceptable salt thereof and a pharmaceutically active derivative thereof, wherein R ¹ and R ² are as defined above (dashed lines indicate the optional presence of a double bond).

Another example includes compounds of Formula (IV), (V) and (VI):

R ¹ is selected from the group consisting of hydrogen, halogen, cyano, C ₁ -C ₆ -alkyl, C ₁ -C ₆ -alkoxy, acyl, alkoxy carbonyl, wherein R ² is as defined above. In a specific embodiment, R ² is an amino moiety.

Another aspect of the invention is the use of a new compound of formula (II), (II-a), (III), (IV), (V) or (VI) as a medicament.

Another aspect of the invention is a pharmaceutical composition comprising at least one thiazolidinone-vinyl conjugated-benzene derivative according to formula (II), (III), (IV), (V) or (VI).

Another aspect of the present invention relates to formula (II), (III), (IV), (V) or (VI) for the preparation of a medicament for the prevention and / or treatment of diseases regulated by PI3 kinase, in particular PI3 kinase γ. The use of the compound according to).

Specific diseases include or may include autoimmune and / or inflammatory diseases, cardiovascular disease, degenerative neuropathy, bacterial or viral infections, kidney disease, platelet aggregation, cancer, transplant complications due to rejection, graft rejection or lung injury, etc. It is selected from the group consisting of.

In a preferred embodiment, the compounds are used for the treatment of autoimmune diseases or inflammatory diseases such as multiple sclerosis, psoriasis, rheumatoid arthritis, systemic lupus erythematosus, inflammatory bowel disease, pulmonary inflammation, thrombosis or brain infections / inflammatory diseases such as meningitis or encephalitis and Useful for prevention.

In another preferred embodiment according to the invention, these compounds are useful for the treatment and / or prophylaxis of degenerative neurological diseases including multiple sclerosis, Alzheimer's disease, Huntington's disease, central nervous system trauma, stroke or ischemic disease.

In a particularly preferred embodiment according to the invention, these compounds are useful for the treatment and / or prophylaxis of cardiovascular diseases such as atherosclerosis, cardiac hypertrophy, cardiomyocyte dysfunction, blood pressure rise or vasoconstriction.

In another particularly preferred embodiment according to the present invention, the compounds are used for chronic obstructive pulmonary disease, anaphylactic shock due to rejection, graft rejection, glomerulosclerosis, glomerulonephritis, progressive kidney fibrosis, endothelial and epithelial injury of lung or general pulmonary airway inflammation Fibrosis, psoriasis, allergic diseases, asthma, paralytic or ischemic disease, ischemia-reperfusion, platelet aggregation / activation, skeletal muscle atrophy / hypertrophy, leukocyte recruitment in cancer tissues, angiogenesis, metastasis in particular, melanoma, carphos sarcoma, Useful for the treatment and / or prevention of acute and chronic bacterial and viral infections, pneumonia, transplant complications.

According to the invention, the compounds of formula (II), (II-a), (III), (IV), (V) or (VI) modulate, in particular inhibit, PI3 kinase activity and more particularly PI3Kγ activity. It is suitable.

Another object of the present invention is to formulate (II), (II-a), (III), as well as azolidinone-vinyl conjugated-benzene derivatives of formula (I), (Ia), (Ic) or (Id), It is to provide a method for producing a thiazolidinone-vinyl conjugated-benzene derivative according to (IV), (V) or (VI).

Azolidinone-vinyl conjugated-benzene derivatives exemplified in the present invention can be prepared from readily available starting materials using the following general methods and procedures. Given typical or preferred experimental conditions (ie reaction temperature, time, moles of reagent, solvent, etc.), other experimental conditions may also be used unless otherwise stated. Optimum reaction conditions may vary depending on the particular reagent or solvent used, but such conditions can be determined by one skilled in the art using routine procedures.

In the method described in the following schemes, R ¹ , R ² G, V, W, Y ¹ , Y ² , Z, m, n, o, p and q are each as defined above in the detailed description.

In general, the azolidinone-vinyl conjugated-benzene derivatives according to formula (I) are obtained by conventional methods or by microwave assisted techniques, by some common synthetic methods using liquid- and solid-phase chemistry protocols. (Brummond et.al., JOC , 64, 1732-1726 (1999)).

Scheme 1

Schematic 2

In the first step, an equal molar amount of aldehyde reactant P1 (P1a) and compound 2 (particularly thiazolidinedione or rhodanin P3) are heated, preferably in the presence of a mild base. To prepare an olefin corresponding to formula (Ia). In the first step, Pla is substituted by the precursors Plb and Plc to obtain the final compounds (Ib) and (Ic), respectively, as detailed above.

Particularly preferred processes according to the invention are illustrated by the following schemes 3 and 4, wherein the compounds of the formulas (II) and (III) are each obtained using the reactions as mentioned above.

Scheme 3

Scheme 4

This step can be carried out in solvent-free conditions at a sufficiently high temperature at which the reaction mixture can at least partially melt, but is preferably carried out in the presence of an inert solvent. Preferable temperature range is about 100 to 250 degreeC, and especially preferable temperature is a temperature of about 120 to 200 degreeC. Examples of the solvent for the reaction include solvents such as dimethoxymethane, xylene, toluene, o-dichlorobenzene and the like. Examples of suitable mild bases for the reaction include alkali and alkaline earth metal salts of weak acids such as (C ₁ -C ₁₂ ) -alkyl carboxylic acids and benzoic acid, calcium carbonate, magnesium carbonate, potassium bicarbonate alkali and alkaline earth carbonates and bicarbonates, and tertiary amines such as pyridine, triethylamine, diisopropylethylamine, N-methylmorpholine, N-ethylpiperidine, N-methylpiperidine, and the like As well as secondary amines such as piperidine and morpholine. Particularly preferred mild bases are sodium acetate or piperidine in terms of economy and efficiency.

In such typical reactions (Tietze et. Al., In "The Knoevenagel reaction", p. 341 ff., Pergamon Press, Oxford 1991, Eds /: Trost BM, Fleming I.), the aldehyde starting materials P1a and other starting compounds ( For example, thiazolidinedione) P3 is bound by about 0.5 equimolar amounts to 1 equivalent of piperidine in dimethoxymethane or a similar solvent and heated between about 120 to 200 ° C., at this temperature for about 15 minutes to 3 In time the reaction is substantially complete. If the desired olefin of formula (Ia) is precipitated out of the reaction mixture by cooling, for example by mixing with water and by continuous filtration, it is separated by filtration to give a crude product and, if necessary, It is purified by crystallization or standard chromatography methods.

Other compounds of formula (Ia) are typically obtained by mixing thiazolidinedione P3 with an equal molar amount of aldehyde P1a and an excess molar, preferably 2-4 times anhydrous sodium acetate. The mixture is heated at a temperature high enough to give a melting effect, at which temperature the reaction is usually completed in 5 to 60 minutes.

Preferably the reaction is carried out in an acidic medium such as acetic acid in the presence of sodium acetate or beta-alanine.

The reactions described above may also be carried out under microwave conditions as a heating source. Typically the aldehyde starting materials P1a and thiazolidinedione P3 are combined at about 0.5 equimolar equivalents to 1 equivalent of piperidine in dimethoxymethane or similar solvents and heated at a temperature between 140 and 240 ° C. at this temperature Is substantially completed in 3 to 10 minutes.

Pharmaceutically acceptable cationic salts of the present invention can be readily prepared by reacting the acidic forms in a suitable base, usually 1 equivalent, in a co-solvent. Typical bases are sodium hydroxide, sodium methoxide, sodium ethoxide, sodium hydride, potassium hydroxide, potassium methoxide, magnesite Calcium Hydroxide, Calcium Hydroxide, Benzathine, Choline, Diethanolamine, Ethylenediamine, Meglumine, Benethamine, Diethylamine, Piperazine and Tromethamine )to be. The salts are separated by addition of concentration to dryness or non-solvent. In some cases, the salts are mixed with an acidic solution and a cationic solution (sodium ethylhexanoate, magnesium oleate) and employ a solvent in which the desired cationic salts precipitate, or otherwise concentrate or cost. It can be separated by the addition of a hawk.

2,4-azolidinone derivatives P3 are commercially available from various sources. Aldehydes of the formula P1a are prepared by various well-known methods, for example, with corresponding carboxylic acid alkyl esters or carboxylic acids as starting materials, by oxido-reduction, ie lithium aluminum hydrides of carboxylic acid alkyl esters or carboxylic acids, Mild oxidation or ternary oxidation with diisopropylaluminum, etc., reduced to benzyl alcohol and using reagents such as manganese dioxide, chromic acid, Dess-Martin reagent (Swern oxidation), or under conditions known to produce aldehydes from primary alcohols, by oxidation-reduction using standard techniques to reoxidize benzyl alcohol to the corresponding aldehyde. Another method is to directly reduce the corresponding carboxylic acid alkyl ester or carboxylic acid to the corresponding aldehyde using DIBAL at low temperature or by other techniques known in the art.

Scheme 5

Another method of preparing suitable aldehydes is to selectively reduce the nitrile moiety to the corresponding aldehyde using known methods such as, for example, DIBAL and the like. Another method of preparing aldehydes of formula Pla is to selectively reduce the corresponding acyl chlorides using, for example, lithium aluminum-tri-tert-butoxyhydride (Cha JS Brown HC, JOC 1993, 58, p. 4732-34). Another method for preparing suitable aldehydes is to react the corresponding benzene derivatives in a Friedl-Crafts type of reaction, wherein the substrate P4 shown in Scheme 5 is titanium tetrachloride. react with 1,1-dichloromethylmethyl ether in the presence of titanium tetrachloride or aluminum trichloride or any corresponding Lewis acid suitable for such a reaction.

According to a more preferred method of the invention, as described in (Petrov OI, Kalcheva VB, Antonova AT, Collect. Czech Republic, Chem. Commun, 62, p. 494-7 (1991)) and subsequently described by Scheme 6 Reactant P2 is obtained by reaction with 1,1-dichloromethylmethyl ether as described above starting from P5.

Scheme 6

Another more preferred method of the invention is that reactant P6 is obtained by reaction with other DMF by way of magnesium or n- butyl-lithium or by methods known to those skilled in the art, as illustrated by Scheme 7 below.

Scheme 7

Another more preferred method of the present invention is that reactant P6 is reacted with n- butyl-lithium or LDA in the presence of a suitable electrophile R ¹ -X, starting from P9, as illustrated by Scheme 8 below. Or by another method known to those skilled in the art.

Scheme 8

Similarly, the saturated precursor P6 can be obtained in a one-pot reaction using P9 and appropriate electrophiles R ¹ -X and R ² -X as set forth in Scheme 9.

Scheme 9

If the general synthetic methods set out above are inadequate for obtaining the compound according to formula (I) and / or for obtaining the intermediates necessary for the synthesis of the compound of formula (I), suitable preparation methods known to those skilled in the art should be used. In general, the synthetic routes to any individual compound of formula (I) will depend on the specific substituents of each molecule and the readily available intermediates required; Such factors are also known to those skilled in the art.

For all protection and deprotection methods, see Philip J. Kocienski, in "Protecting Groups" , Georg Thieme Verlag Stuttgart, New York, 1994 and Theodora W. Greene and Peter GM Wuts in "Protective Groups in Grganic Synthesis ", Wiley Interscience, 3rd edition 1999.

Compounds of the present invention can be separated in relation to solvent molecules by evaporating a suitable solvent to crystallize. Pharmaceutically acceptable acid addition salts of the compounds of the present invention, including basic centers, can be prepared by conventional methods. For example, the free base solution is treated with a suitable acid in a pure solution or a suitable solution, and the salts obtained are separated by evaporation or filtration of the reaction solvent under vacuum. Pharmaceutically acceptable base addition salts can be obtained by analogous methods of treating a solution of a compound of the present invention with a suitable base. Both types of salts can be formed or interconverted using ion-exchange resin technology.

When employed pharmaceutically, the azolidinedione-vinyl conjugated-benzene derivatives of the invention are typically administered in the form of pharmaceutical compositions. Therefore, pharmaceutical compositions comprising the compounds of the present invention, pharmaceutically acceptable carriers, diluents or excipients are also within the scope of the present invention. One skilled in the art recognizes all kinds of carriers, diluents or excipient compounds suitable for preparing pharmaceutical compositions.                 

The compounds of the present invention may be provided in the form of pharmaceutical compositions and their unit dosages, together with conventionally used auxiliaries, carriers, diluents or excipients, which may be in the form of tablets or filled capsules and solids, or solutions Liquids such as suspensions, suspensions, emulsions, elixirs, or capsules filled with the same may be used, all of which are oral and in the form of sterile injectable solutions for parenteral use (including subcutaneous use). Can be used as Such pharmaceutical compositions and unit dosage forms thereof contain components in conventional proportions with or without additional active compounds or principals, and such unit dosage forms may be in effective amounts in proportion to the intended daily dosage range to be used. It may contain the active ingredients of.

Pharmaceutical compositions comprising azolidinedione-vinyl conjugated-benzene derivatives of the present invention may be prepared by methods well known in the pharmaceutical art and comprise at least one active compound. In general, the compounds of the present invention are administered in a pharmaceutically effective amount. The amount of compound administered substantially will typically be determined by the physician according to the circumstances involved, including the condition to be treated, the route of administration chosen, the actual compound administered, age, weight and patient's response, the severity of the patient's symptoms, and the like.

The pharmaceutical compositions of the invention can be administered by a variety of routes including oral, rectal, transdermal, subcutaneous, intravenous, intramuscular and intranasal. have. Compositions for oral administration may be in the form of a bulk liquid solution, suspension or bulk powder. More generally, however, the compositions are easy to provide in precise dosage form in unit dosage form. The term “unit dosage form” refers to units that are suitably physically separated as a single dose for humans and other mammals, each unit having a prescribed amount of activity calculated to give the desired therapeutic effect with respect to the appropriate pharmaceutical excipient. Contains substances. Typical unit dose forms include ampoules or injections, which are prefilled with pills, tablets, capsules, etc., in the case of liquid compositions or solid compositions. In such compositions, the thiazolidinedione-vinyl conjugated-benzene derivative is usually a minor component (about 0.1 to about 50 weight percent or preferably about 1 to 40 weight percent), with the remainder being a variety of vehicles or carriers. And processing aids which aid in making the desired formulation.

Liquid forms suitable for oral administration may include suitable water-soluble or non-aqueous carriers with buffers, suspending and dispensing agents, colorants, flavors, and the like. Solid forms may include, for example, any of the following components or compounds of similar nature: microcrystalline cellulose, gum tragacanth or gelatin; Excipients such as starch or lactose, disintegrating agents such as alginic acid, primogel, or corn starch; Lubricants such as magnesium stearate; Colloidal silicon dioxide; Sweetening agents such as sucrose or saccharin, flavoring agents such as peppermint, methyl salicylate or orange flavor.

Injectable compositions are typically based on injectable sterile saline or phosphate-buffered saline or other injectable carriers known in the art. As mentioned above, in such compositions the thiazolidinedione-vinyl conjugated-benzene derivative of formula (I) is typically a minor component, often 0.05-10% by weight and the remainder is an injectable carrier and the like.

The aforementioned ingredients for oral administration or injectable compositions are merely representative. Other materials, as well as processing techniques, are found in Part 5 of Remington's Pharmaceutical Science (20th Edition, 2000; Marck Publishing Company, Easton, Pennsylvania) and are described together herein by reference.

The compounds of the present invention may also be administered in sustained release form or from a sustained release drug delivery system. A description of representative sustained release substances can also be found in the literature incorporated in Remington's Pharmaaceutical Sciences .

In the following the invention is described by way of example, which are not to be construed as limiting the scope of the invention. The following abbreviations are then used in the following examples: min (minutes), hr (hours), g (grams), mmol (mmole), mp (melting point), eq (equivalent), ml (ml), μl (micro) Liters), ACN (acetonenitrile), Boc (butoxycarbonyl), Cbz (carboxybenzyl), CDCl ₃ (dichloromethane), cHex (cyclohexane), dba (dibenzylideneacetone), DCM (dichloromethane), DEAD (diethylazodicaboxylate), DIC (diisopropyl carbodiimide), DIEA (diisopropylethylamine), DMAP (4-dimethylaminopyridine), DME (dimethoxyethane), DMF (Dimethylformamide), DMSO (dimethylsulfoxide), DMSP- d ₆ (deuterated dimethylsulfoxide), EDC (1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride), EtOAc ( ethyl acetate), Et ₂ O (diethyl ether), Fmoc (9- fluorenylmethoxycarbonylamino ethoxy-carbonyl: 9-flurenylmethoxy-carbonyl), HOBt (1- hydroxybenzotriazole), K ₂ CO ₃ ( Potassium), MgSO ₄ (magnesium sulfate), MsCl (methylsulfonyl chloride), MTBE (tert - butyl methyl ether), NaH (Sodium hydride), NaHCO ₃ (sodium bicarbonate), (n- butyllithium nBuLi) , PCC (pyridinium chlorochromate), PE (petroleum ether), QCI (tetrabutylammonium chloride), rt (room temperature), TBTU ( O -benzotriazolyl- N, N, N ', N' -tetra Methyluronium-tetrafluoroborate: O-benzotriazolyl- N, N, N ', N'-termethyluronium-tetrafluoroborate), TEA (triethylamine), TFA (trifluoroacetic acid), THF (tetrahydrofuran), TMOF (trimethylorthoformate), TMAD ( N, N, N ', N' -tetramethylazodicarboxamide: N, N, N', N ' -tetramethylazodicarboxamide), TosCl (toluenesulfonyl chloride) .

The following list of compounds was synthesized according to the methods mentioned below.

Example name

1 5- (1,3-benzodioxol-5-ylmethylene) -1,3-thiazolidine-2,4-dione                 

2 5- (1,3-benzodioxol-5-ylmethylene) -2-thioxo-1,3-thiazolidin-4-one

3- 5- (2,3-dihydro-1,4-benzodioxin-6-ylmethylene) -1,3-thiazolidine-2,4-dione

4 5- (2,3-dihydro-1-benzofuran-1-benzofuran-5-ylmethylene) -1,3-thiazolidine-2,4-dione

5 5-[(7-methoxy-1,3-benzodioxol-5-yl) methylene] -1,3-thiazolidine-2,4-dione

6 5-[(9,10-dioxo-9,10-dihydroanthracen-2-yl) methylene] -1,3-thiazolidine-2,4-dione

7 (5-[(2,2-difluoro-1,3-benzodioxol-5-yl) methylene] -1,3-thiazolidine-2,4-dione

8 (5Z) -5- (1,3-dihydro-2-benzofuran-5-ylmethylene) -1,3-thiazolidine-2,4-dione

9 5- (1-benzofuran-5-ylmethylene) -1,3-thiazolidine-2,4-dione

10 5-[(4-methyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6-yl) methylene] -1,3-thiazolidine-2,4-dione

11 5- (1,3-benzodioxol-5-ylmethylene) -2-imino-1,3-thiazolidin-4-one

12 5-quinolin-6-ylmethylene-thiazolidine-2,4-dione

13 5-quinolin-6-ylmethylene-2-thioxo-thiazolidin-4-one

14 2-imino-5-quinolin-6-ylmethylene-thiazolidin-4-one                 

15 5- (3-Methyl-benzo [d] isoxazol-5-ylmethylene) -thiazolidine-2,4-dione

16 5- (4-phenyl-quinazolin-6-ylmethylene) -thiazolidine-2,4-dione

17 5- (4-dimethylamino-quinazolin-6-ylmethylene) -thiazolidine-2,4-dione

18 5-[(4-aminoquinazolin-6-yl) methylene] -1,3-thiazolidine-2,4-dione

19 5-[(4-piperidin-1-ylquinazolin-6-yl) methylene] -1,3-thiazolidine-2,4-dione

20 5-[(4-morpholin-4-ylquinazolin-6-yl) methylene] -1,3-thiazolidine-2,4-dione

21 5-{[4- (benzylamino) quinazolin-6-yl] methylene-1,3-thiazolidine-2,4-dione

22 {[4- (diethylamino) quinazolin-6-yl] methylene} -1,3-thiazolidine-2,4-dione

23 5-({4-[(pyridin-2-ylmethyl) amino] quinazolin-6-yl} methylene) -1,3-thiazolidine-2,4-dione

24 5-({4-[(pyridin-3-ylmethyl) amino] quinazolin-6-yl} methylene) -1,3-thiazolidine-2,4-dione

25 ethyl 1- {6-[(2,4-dioxo-1,3-thiazolidine-5-ylidene) methyl] quinazolin-4-yl} piperidine-3-carboxylate

26 ethyl 1- {6-[(2,4-dioxo-1,3-thiazolidine-5-ylidene) methyl] quinazolin-4-yl} piperidine-4-carboxylate                 

27 tert-butyl 1- {6-[(2,4-dioxo-1,3-thiazolidin-5-ylidene) methyl] quinazolin-4-yl} -L-prolinate

28 5-{[4- (4-methylpiperazin-1-yl) quinazolin-6-yl] methylene} -1,3-thiazolidine-2,4-dione

29 5-{[4- (4-pyrimidin-2-ylpiperazin-1-yl) quinazolin-6-yl] methylene} -1,3-thiazolidine-2,4-dione

30 5-({4- [4- (4-fluorophenyl) piperidin-1-yl] quinazolin-6-yl} methylene) -1,3-thiazolidine-2,4-dione

31 5-{[4- (4-benzylpiperidin-1-yl) quinazolin-6-yl] methylene} -1,3-thiazolidine-2,4-dione

32 5-({4- [4- (2-phenylethyl) piperidin-1-yl] quinazolin-6-yl} methylene-1,3-thiazolidine-2,4-dione

33 5-{[4- (4-methylpiperidin-1-yl) quinazolin-6-yl] methylene} -1,3-thiazolidine-2,4-dione

34 5-{[4- (4-hydroxypiperidin-1-yl) quinazolin-6-yl] methylene} -1,3-thiazolidine-2,4-dione

35 1- [6- (2,4-Dioxo-thiazolidine-5-ylidenemethyl) -quinazolin-4-yl] -piperidine-4-carboxylic acid

36 1- [6-2,4-dioxo-thiazolidine-5-yldinemethyl) -quinazolin-4-yl] -piperidine-3-carboxylic acid                 

37 1- [6- (2,4-dioxo-thiazolidine-5-ylidenemethyl) -quinazolin-4-yl] -pyrrolidine-2-carboxylic acid

38 5- (4-Methylamino-quinazolin-6-ylmethylene) -thiazolidine-2,4-dione

39 5- (4-methoxy-quinazolin-6-ylmethylene) -thiazolidine-2,4-dione

40 2-imino-5- (4-methylamino-quinazolin-6-ylmethylene) -thiazolidin-4-one

41 2-Imino-5- (4-piperidine-quinazolin-6-ylmethylene) -thiazolidin-4-one

42 2-Imino-5- (4-dimenylamino-quinazolin-6-ylmethylene) -thiazolidin-4-one

43 5- (2-Methyl-2H-benzotriazol-5-ylmethylene) -thiazolidine-2,4-dione

44 5- (3-Methyl-3H-benzotriazol-5-ylmethylene) -thiazolidine-2,4-dione

45 5- (3-ethyl-3H-benzoimidazol-5-ylmethylene) -thiazolidine-2,4-dione

46 5-{[1- (4-phenylbutyl) -1H-benzimidazol-6-yl] methylene} -1,3-thiazolidine-2,4-dione

47 5-[(1-prop-2-yn-1-yl-1H-benzimidazol-6-yl) methylene] -1,3-thiazolidine-2,4-dione

48 5-[(1- {2- [4- (trifluoromethyl) phenyl] ethyl} -1H-benzimidazol-6-yl) methylene] -1,3-thiazolidine-2,4-dione

49 5 ({1- [2- (4-hydroxyphenyl) ethyl] -1H-benzimidazol-6-yl} methylene-1,3-thiazolidine-2,4-dione                 

50 methyl 4- {6-[(2,4-dioxo-1,3-thiazolidine-5-ylidene) methyl] -1H-benzimidazol-1-yl} cyclohexanecarboxylate

51 5-({1- [2- (5-methoxy-1H-indol-3-yl) ethyl] -1H-benzimidazol-6-yl} methylene) -1,3-thiazolidine-2, 4-dion

52 5-({1-[(1-methyl-1H-pyrazol-4-yl) methyl] -1H-benzimidazol-6-yl} methylene) -1,3-thiazolidine-2,4- Dion

53 5-({1- [2- (3,4-dimethoxyphenyl) ethyl] -1H-benzimidazol-6-yl} methylene-1,3-thiazolidine-2,4-dione

54 5 ({1- [2- (4-phenoxyphenyl) ethyl] -1H-benzimidazol-6-yl} methylene) -1,3-thiazolidine-2,4-dione

55 5-({1- [4- (trifluoromethyl) benzyl] -1H-benzimidazol-6-yl} methylene-1,3-thiazolidine-2,4-dione

56 4- {6-[(2,4-dioxo-1,3-thiazolidine-5-ylidene) methyl] -1H-benzimidazol-1-yl} cyclohexanecarboxylic acid

57 5-[(1-isobutyl-1H-benzimidazol-6-yl) methylene] -1,3-thiazolidine-2,4-dione

58 5-({1- [2- (1,3-benzodioxol-4-yl) ethyl] -1 H-benzimidazol-6-yl} methylene) -1,3-thiazolidine-2,4 Dion

59 5-({1- [2- (2-phenoxyphenyl) ethyl] -1H-benzimidazol-6-yl} methylene) -1,3-thiazolidine-2,4-dione                 

60 5-{[1- (3,3-diphenylpropyl) -1H-benzimidazol-6-yl] methylene-1,3-thiazolidine-2,4-dione

61 5-{[1- (2-methoxybenzyl) -1H-benzimidazol-6-yl] methylene} -1,3-thiazolidine-2,4-dione

62 5-{[1- (3-furylmethyl) -1H-benzimidazol-6-yl] methylene} -1,3-thiazolidine-2,4-dione

63 5-[(1-propyl-1H-benzimidazol-6-yl] methylene} -1,3-thiazolidine-2,4-dione

64 5-quinoxaline-6-ylmethylene-thiazolidine-2,4-dione

65 5-quinoxalin-6-ylmethylene-2-thioxo-thiazolidin-4-one

66 2-imino-5-quinoxalin-6-ylmethylene-thiazolidin-4-one

67 5-benzothiazol-6-ylmethylene-thiazolidine-2,4-dione

68 5- (3-Methyl-benzofuran-5-ylmethylene) -thiazolidine-2,4-dione

69 5- (2-Bromo-3-methyl-benzofuran-5-ylmethylene) -thiazolidine-2,4-dione

70 5- (3-Bromo-benzofuran-5-ylmethylene) -thiazolidine-2,4-dione

71 3- [5- (2,4-dioxo-thiazolidine-5-ylidenemethyl) -benzofuran-3-yl] -acrylic acid ethyl ester

72 3- [5- (2,4-dioxo-thiazolidine-5-ylidenemethyl) -benzofuran-3-yl] -acrylic acid

73 5- [3- (3-oxo-3-piperidine-1-propenyl) -benzofuran-5-ylmethylene] -thiazolidine-2,4-dione

74 Methyl 1-((3- {5-[(2,4-dioxo-1,3-thiazolidin-5-ylidene) methyl] -1-benzofuran-3-yl} prop-2- Enoyl) Prolinenate

75 methyl 1-((3- {5-[(2,4-dioxo-1,3-thiazolidin-5-ylidene) methyl] -1-benzofuran-3-yl} prop-2- Enoyl) -D-prolinenade

76 (5-({3-[(3-oxo-3-pyrrolidin-1-ylprop-1-en-yl] -1-benzofuran-5-yl} methylene) -1,3-thia Zolidine-2,4-dione

77 5 ({3- [3-morpholin-4-yl-3-oxoprop-1-en-1-yl] -1-benzofuran-5-yl} methylene-1,3-thiazolidine- 2,4-dione

78 Methyl 1- (3- {5-[(2,4-dioxo-1,3-thiazolidin-5-ylidene) methyl] -1-benzofuran-3-yl} prop-2-eno (L) -L-prolinate

79 N-cyclohexyl-3- {5-[(2,4-dioxo-1,3-thiazolidin-5-ylidene) methyl] -1-benzofuran-3-yl} -N-methylacrylic amides

80 3- {5-[(2,4-dioxo-1,3-thiazolidine-5-ylidene) methyl] -benzofuran-3-yl} -N-ethyl-N- (2-hydroxy Ethyl) acrylamide

81 N-cyclobutyl-3- {5-[(2,4-dioxo-1,3-thiazolidin-5-ylidene) methyl] -1-benzofuran-3-yl} acrylamide

82 5-({3- [3-azetidin-1-yl-3-oxoprop-1-en-1-yl] -1-benzofuran-5-yl} methylene) -1,3-thiazoli Dean-2,4-dione

83 5-({3- [3- (1,3-dihydro-2H-isoindol-2-yl) -3-oxoprop-1- en-1-yl] -1-benzofuran-5- Methylene-1,3-thiazolidine-2,4-dione

84 5-({3- [3-Azepan-1-yl-3-oxoprop-1-en-1-yl] -benzofuran-5-yl} methylene) -1,3-thiazolidine- 2,4-dione

85 3- {5-[(2,4-dioxo-1,3-thiazolidin-5-ylidene) methyl] -1-benzofuran-3-yl} -N-piperidin-1-yl Acrylamide

86 3- {5-[(2,4-dioxo-1,3-thiazolidine-5-ylidene) methyl] -1-benzofuran-3-yl} -N- (pyridin-3-ylmethyl Acrylamide

87 N-cyclohexyl-3- {5-[(2,4-dioxo-1,3-thiazolidin-5-ylidene) methyl] -1-benzofuran-3-yl} acrylamide

88 5-({3- [3- (4-methylpiperazin-1-yl) -3-oxoprop-1-en-1-yl] -benzofuran-5-yl} methylene-1,3- Thiazolidine-2,4-dione

89 N-cycloheptyl-3- {5-[(2,4-dioxo-1,3-thiazolidin-5-ylidene) methyl] -1-benzofuran-3-yl} acrylamide

90 5 ({3- [3- (2,5-Dihydro-1H-pyrrol-1-yl) -3-oxoprop-1-en-1-yl] -1-benzofuran-5-yl} Methylene) -1,3-thiazolidine-2,4-dione

91 N-cyclopentyl-3- {5-[(2,4-dioxo-1,3-thiazolidin-5-ylidene) methyl] -1-benzofuran-3-yl} acrylamide

92 3- [5- (2,4-dioxo-thiazolidine-5-ylidenemethyl) -benzofuran-3-yl] -propionic acid ethyl ester

93 3- [5- (2,4-dioxo-thiazolidine-5-ylidenemethyl) -benzofuran-3-yl] -propionic acid

94 5- [3- (3-oxo-3-piperidin-1-yl-propyl) -benzofuran-5-ylmethylene] -thiazolidine-2,4-dione

95 6- (2,4-dioxo-thiazolidine-5-ylidenemethyl) -2,3-dihydro-benzo [1,4] oxazine-4-carboxylic acid tert-butyl ester

96 5- (3,4-Dihydro-2H-benzo [1,4] oxazin-6-ylmethylene) -thiazolidine-2,4-dione

97 5- (4-benzoyl-3,4-dihydro-2H-benzo [1,4] oxazin-6-ylmethylene) -thiazolidine-2,4-dione

98 5- (4-acetyl-3,4-dihydro-2H-benzo [1,4] -oxazin-6-ylmethylene) -thiazolidine-2,4-dione

99 6- (2,4-dioxo-thiazolidine-5-ylidenemethyl) -benzo [1,4] oxazine-4-carboxylic acid tert-butyl ester

100 [6- (2,4-dioxo-thiazolidine-5-ylidenemethyl) -3-oxo-2,3-dihydro-benzo [1,4] -oxazin-4-yl] -acetic acid Methyl ester

101 N-benzyl-2- [6- (2,4-dioxo-thiazolidine-5-ylidenemethyl) -3-oxo-2,3-dihydro-benzo [1,4] oxazine-4 -Yl] -acetamide

102 5- (4-Butyl-3-oxo-3,4-dihydro-2H-benzo [1,4] oxazin-6-ylmethylene) -thiazolidine-2,4-dione

103 5- (4-benzyl-3-oxo-3,4-dihydro-2H-benzo [1,4] oxazin-6-ylmethylene) -thiazolidine-2,4-dione

104 5- (2-chloro-benzofuran-5-ylmethylene) -thiazolidine-2,4-dione

105 5- (3-amino-benzo [d] isoxazol-5-ylmethylene) -thiazolidine-2,4-dione

106 5- (3-phenylethynyl-benzofuran-5-ylmethylene) -thiazolidine-2,4-dione

107 5-benzo [1,2,5] thiadiazol-5-ylmethylene-thiazolidine-2,4-ion

108 5-benzo [1,2,5] oxadiazol-5-ylmethylene-thiazolidine-2,4-ion

109 5 (2-Methyl-benzofuran-6-ylmethylene) -thiazolidine-2,4-dione

110 5- (2-carboxymethyl-benzofuran-6-ylmethylene) -thiazolidine-2,4-dione

111 5- (3-Bromo-2-fluoro-2,3-dihydro-benzofuran-6-ylmethylene) -thiazolidine-2,4-dione

112 5- (2-Fluoro-benzofuran-6-ylmethylene) -thiazolidine-2,4-dione

The following intermediate aldehydes are commercially available: 2,2-difluoro-1,3-benzodioxol-5-carbaldehyde, 1,3-benzodioxol-5-carboxaldehyde, 1,4-benzo Dioxane-6-carboxaldehyde, 9,10-dioxo-dihydro-anthracene-2-carbaldehyde, 2,3-dihydro-benzo [b] furan-5-carboxaldehyde, 3-methoxy- 4,5-methylenedioxybenzaldehyde.

Thiazolidinedione and rhodanine are commercially available. Intermediate aldehydes were synthesized according to the protocols described below.                 

HPLC, NMR and MS data described in the following examples were obtained as follows: HPLC: Column Waters Simmetry C8 50 × 4.6 mm, Conditions: a- MeCN / H ₂ O 0.09% TFA, 0-100% ( 10 minutes); b- MeCN / H ₂ O, 5-100% (8 min), maximum plot 230-400 nm; Mass spectroscopy: PE-SCIEX API 150 EX (APCI and ESI), LC / MS spectroscopy: Waters ZMD (ES); ¹ H NMR: Bruker DPX-300 MHz.

Purification consisted of the following: Columns Prep Nova-Pak ^? Prepared HPLC Waters Prep LC 4000 with HR C186 μm 60 μs, 40 × 30 mm (up to 100 mg) or 40 × 300 mm (up to 1 g). All purifications were performed with a gradient of MeCN / H ₂ O 0.09% TFA.

Intermediate 1: Preparation of 5-formyl-1-benzofuran

Step I: Ethyl-2-formyl-4-bromophenoxy acetate:

A mixture of 5-bromosalicylaldehyde (50 g, 0.248 mol), ethyl bromoacetate (42 g, 0.248 mol) and K ₂ CO ₃ (68 g, 0.49 mol) in dry DMF (200 mL) was stirred at room temperature for 12 hours. . The reaction mixture was filtered and the filtrate was diluted with water. The mixture was extracted with diethyl ether (4 × 200 mL), washed with brine and concentrated to give crude ethyl-2-formyl-4-bromophenoxy acetate (64 g, 90%) as a solid.

Step II: 4-Bromo-2-formylphenoxy acetic acid:

A mixture of ethyl-2-formyl-4-bromophenoxy acetate (60 g, 0.209 mol), LiOH (7.5 g, 0.31 mol), THF (250 mL) and water (100 mL) was stirred at rt for 24 h. The reaction mixture was concentrated under reduced pressure and the residue was adjusted to pH = 2 by acidification with 1.5N HCl. The solid precipitate obtained was filtered and dried to give 4-bromo-2-formylphenoxy acetic acid (50 g, 94%).

Step III: 5-Bromo-1-benzofuran:

To a mixture of 2-formyl-4-bromophenoxy acetic acid (50 g, 0.192 mol) and sodium acetate (100 g, 1.21 mol) in acetic acid (250 mL) at 100 ° C. was added in portions over 3 hours. . The reaction mixture was then refluxed for 20 hours. The solvent was distilled off and the residue was diluted with 3N HCl (500 mL) and refluxed for 2 hours. The reaction mixture was concentrated in vacuo and the product extracted with petroleum ether (3x200 mL). The organic layer was washed with 10% NaHCO ₃ solution and evaporated to afford 5-bromo-1-benzofuran (15 g, 40%) as a pale yellow liquid.

Step IV: 5-formyl-1-benzofuran (Pla of Scheme 2 in Example 9):

A mixture of 5-bromo-1-benzofuran (0.5 g), Mg (0.92 g, 0.038 mol), I ₂ (1 crystal) in dry THF (2.5 mL) under reflux was refluxed for 30 minutes. As soon as the I ₂ color disappeared, a solution of 5-bromo-1-benzofuran (4.5 g) in 25 mL of dry THF was added and refluxed for a further 2 hours. The reaction mixture was then cooled to −40 ° C., dried DMF (3.6 g) was added dropwise and slowly warmed to room temperature for 12 hours. The reaction mixture was cooled to 0 ° C., acidified with 3N HCl to pH = 2 and stirred for 30 minutes. The reaction mixture was diluted with water (500 mL), extracted with ethyl acetate (2 × 200 mL), washed with brine and dried. The solvent was removed in vacuo and purified by column chromatography on silica gel (petroleum ether / CH ₂ Cl ₂ ) to give 5-formyl-1-benzofuran (2 g, 54%) as a liquid. LC-MS: M / Z ESI: 1.47 min, 147.34 (M + l).

Intermediate 2: 4-Methyl-3-oxo-3,4-dihydro-2H-benzo [1,4] oxazine-6-carbaldehyde

Step I: 2- (N-methylamino) -phenol:

1 g benzoxazole was dissolved in 20 ml THF. 0.9 g of NaBH ₄ was added under a nitrogen atmosphere and stirred. The suspension was cooled to 0 ° C., 0.86 ml of acetic acid dissolved in 5 ml THF was slowly added and the reaction mixture was kept at 5 ° C. or lower. The reaction was stirred at 0 ° C. for 30 minutes and at room temperature for an additional 12 hours. The reaction mixture was cooled back to 0 ° C. and 50 ml of saturated NH ₄ Cl solution was carefully added. The phases were separated and the aqueous layer was extracted twice with EtOAc. The combined organic layers were washed with brine, dried over MgSO ₄ and filtered. The solvent was removed to yield 0.97 g of pure 2- (N-methylamino) -phenol.

Step II: 4-Methyl-4H-benzo [1,4] oxazin-3-one

After dissolving 1 g of 2- (N-methylamino) -phenol in chloroform, 10 ml of saturated aqueous NaHCO ₃ solution was added. The solution of 1 g of 2-chloroacetyl chloride in acetone was slowly added while stirring this suspension vigorously. The reaction mixture was stirred at rt for 2 h. The layers were separated. The organic layer was washed with water and dried over Na ₂ SO ₄ . After evaporating the solvent, the red oil was dissolved in 30 ml DMF, 1 g of K ₂ CO ₃ was added and the slurry was heated to 70 ° C. for a further 2 hours. Cyclization is followed by TLC. 200 ml EtOAc was added and the organic layer was washed three times with 0.1 N HCl and five times with brine. The remaining organic layer was dried over MgSO ₄ and filtered. EtOAc was removed under reduced pressure to yield 1.45 g of pure 4-methyl-4H-benzo [1,4] oxazin-3-one.

Step III: 4-Methyl-3-oxo-3,4-dihydro-2H-benzo [1,4] oxazine-6-carbaldehyde

1 g AlCl ₃ was suspended in 10 ml DCM and 0.5 ml nitromethane was added to dissolve AlCl ₃ and the solution was cooled to 0 ° C. 4-methyl-4H-benzo [1,4] oxazin-3-one (0.5 g, 3.06 mmol) dissolved in DCM was added to the solution and stirred at 0 ° C. for 15 minutes. To this solution was further added 0.36 ml of bis-chloromethyl-methylether in DCM. The reaction was stirred at 0 ° C. for 15 minutes and at room temperature for 3 hours. The crude reaction mixture was poured onto ice, the layers separated and the organic phase washed with NaHCO ₃ and brine. After drying over MgSO ₄ and filtration, the solvent was evaporated to yield 0.43 g of crude product. The dark oil was purified by flash chromatography using EtOAc and cyclohexane as eluent to afford 4-methyl-3-oxo-3,4-dihydro-2H-benzo [1,4] oxazine-6-carbaldehyde 0.2 g (37%) was obtained as a colorless solid.

HPLC: 2.07 min. LC-MS: M / Z ESI: 1.31 min, 192.28 (M + l).

Intermediate 3: Preparation of 4-methyl-3,4-dihydro-2H-benzo [1,4] oxazine-7-carbaldehyde

Step I: 4-methyl-3,4-dihydro-2H-benzo [1,4] oxazine

0.97 g of 2- (N-methylamino) -phenol was dissolved in 50 ml acetone, followed by ₂ g of K ₂ CO ₃ dissolved in water. To this suspension was added slowly a solution of 2.66 g of dibromoethane in acetone. The reaction mixture was stirred at reflux for 22 hours. Acetone was evaporated, 200 ml of EtOAc was added and the organic layer was washed three times with 0.1 N HCl and three times with brine. The remaining organic layer was dried over MgSO ₄ and filtered. EtOAc was removed under reduced pressure to give 1 g of pure 4-methyl-3,4-dihydro-2H-benzo [1,4] oxazine.

Step II: 4-Methyl-3,4-dihydro-2H-benzo [1,4] oxazine-7-carbaldehyde

4-methyl-3,4-dihydro-2H-benzo [1,4] oxazine was dissolved in 200 μl DMF under argon. POCl ₃ was added under argon. The reaction was heated and the vial was sealed at 90 ° C. for 75 minutes. 1 ml of NaAc in water was added and stirred while brown oil was formed. The oil was extracted with DCM. The organic layer was washed with brine, dried and evaporated to yield 0.18 g (76%) of colorless dry 4-methyl-3,4-dihydro-2H-benzo [1,4] oxazine-7-carbaldehyde. Obtained as a solid.

LC-MS: M / Z ESI: 1.37 min, 178.35 (M + l).

Intermediate 4: 1,3-dihydroisobenzofuran-5-carbaldehyde

Step I: (1,3-Dihydro-isobenzofuran-5-yl) -methanol

Into a round bottom flask equipped with a reflux condenser, 1.0 g of 3-prop-2-ynyloxy-propene and 2.08 g of propazyl alcohol in 10 ml ethanol were added, followed by tris (triphenylphosphine) rhodium chloride (Wilkinson catalyst) at room temperature. ) 9.8 mg was added. The reaction was heated to 70 ° C. while the color of the reaction quickly changed to yellow. After stirring for one day at room temperature, TLC analysis confirmed complete conversion of starting material. The solvent was evaporated, diluted with DCM, extracted with H ₂ O and dried over MgSO ₄ . The brown mixture was purified by flash chromatography using 8/2 cyclohexane / AcOEt as mobile phase to give (1,3-dihydro-isobenzofuran-5-yl) -methanol as a colorless pure solid (0.92 g). , 60%).

Step II: 1,3-dihydroisobenzofuran-5-carbaldehyde

(1,3-Dihydro-isobenzofuran-5-yl) -methanol (440 mg, 2.9 mmol) was dissolved in 20 ml of DCM. 1,1,1-triacetoxy-1,1-dihydro-1,2-benzidoxol-3 (1H) -one (des-martin reagent) (1.3 g, 3.2 mmol) was added and the reaction was Stir at room temperature for 4 hours. The reaction mixture was diluted with ether, extracted twice with NaOH 1N, twice with H ₂ O and dried over MgSO ₄ . The crude product was sufficiently pure and used without further purification.

HPLC: 2.00 min. LC-MS: M / Z ESI: 1.50 min, 149.18 (M + l).

Intermediate 5: Preparation of Quinoline-6-carbaldehyde

Step I: Quinolin-6-yl-methanol

5 g of methyl quinoline-6-carboxylate was dissolved in dry THF. LiAlH ₄ 1M (2 eq.) In THF was added at -20 ° C. under argon. The solution was stirred at this temperature for 1 hour. Isopropanol was added slowly and the crude was filtered through celite and washed with DCM. Concentration gave 3.6 g (85%) of pure alcohol.

HPLC: 1.10 min. LC-MS: M / Z ESI: 0.91 min, 160.43 (M + 1).

Step II: Quinoline-6-carbaldehyde

2 g of quinolin-6-yl-methanol was dissolved in DCM. 15 g of MnO ₂ were added and the reaction mixture was stirred for 5 hours. The crude was filtered through celite and washed extensively with DCM. Concentration gave 1.85 g (93%) of pure aldehyde.

HPLC: 0.8 min. LC-MS: M / Z ESI: 1.07 min, 158.37 (M + l). ¹ H NMR (DMSO-d6) δ 10.19 (s, 1H), 9.06 (t, J = 3 Hz, 1H), 8.6-8.66 (m, 2H), 8.15 (s, 2H), 7.68 (dd, J = 3 Hz , 9 Hz, 1H).

The following intermediates were synthesized using the appropriate starting materials as follows:

Intermediate 6: 3-Methyl-benzo [d] isoxazole-5-carbaldehyde

HPLC: 2.06 min. LC-MS: M / Z ESI: 1.26 min, 162.31 (M + l). ¹ H NMR (DMSO-d6) δ 10.10 (s, 1H), 8.52 (s, 1H), 8.16 (d, J = 12 Hz, 1H), 8.15 (s, 2H), 7.90 (d, J = 9 Hz, 1H ), 2.63 (s, 3 H).

Intermediate 7: Preparation of 4-chloro-quinazolin-6-carboxylic acid methyl ester

Step I: 4-nitro isophthalic acid

A mixture of 3-methyl-4-nitrobenzoic acid (150 g, 0.825 mol), pyridine (1.5 L) and water (1.5 L) was heated to reflux. KMnO ₄ (10 mol) was added in portions to the high temperature reaction mixture and refluxed for 72 hours. The hot reaction mixture was filtered through celite and washed with hot water. The filtrate was concentrated in vacuo and the residue was diluted with water (750 mL) and acidified with concentrated HCl at 0 ° C. The solid obtained was filtered, washed with water and dried in vacuo to afford 4-nitro isophthalic acid (98 g, 56%).

TLC, chloroform / methanol, 7: 3, R _f = 0.2

Step II: 4-Amino Isophthalic Acid

Pd / C (20%) was added to a solution of 4-nitro isophthalic acid (98 g, 0.457 mol) in methanol (5 L) and hydrogenated at room temperature for 4 hours. The reaction mixture was filtered through celite and the filtrate was concentrated in vacuo to afford 4-amino isophthalic acid (72 g, 87%) as a solid.

TLC, chloroform / methanol, 7: 3, R _f = 0.4

Step III: 4-oxo-3,4-dihydroquinazolin-6-carboxylic acid

A mixture of 4-amino isophthalic acid (17 g, 0.093 mol) and formamide (85 mL) was heated to 180 ° C. for 5 hours. The reaction mixture was cooled to rt and acetone was added. The solid precipitate obtained was stirred for 2 hours, filtered and dried to give 4-oxo-3,4-dihydroquinazolin-6-carboxylic acid (11 g, 61%).

TLC, chloroform / methanol, 7: 3, R _f = 0.25

Step IV: 4-oxo-3,4-dihydroquinazolin-6-methyl carboxylate

To a solution of 4-oxo-3,4-dihydroquinazolin-6-carboxylic acid (24 g, 0.126 mol) in dry methanol (800 mL) was added thionyl chloride (37 g) at 5 ° C., and at 80 ° C. for 5 hours. It was refluxed. The reaction mixture was concentrated in vacuo and the crude was dissolved in ethyl acetate (250 mL). The organic layer was washed with 10% NaHCO ₃ aqueous solution, water, brine and dried. The solvent was removed in vacuo to afford 4-oxo-3,4-dihydroquinazolin-6-methyl carboxylate (24 g, 92%) as a solid.

TLC, chloroform / methanol, 8: 2, R _f = 0.6

Step V: Methyl-4-chloroquinazolin-6-carboxylate

A mixture of 4-oxo-3,4-dihydroquinazolin-6-methyl carboxylate (12 g, 0.058 mol) and phosphoryl chloride (180 mL) was heated to reflux for 7 hours. Excess phosphoryl chloride was distilled off and the crude was taken up in ethyl acetate (250 mL). The organic layer was washed with 10% NaHCO ₃ aqueous solution, water, brine and dried. The solvent was removed in vacuo and the crude was purified by column chromatography on silica gel to give methyl-4-chloroquinazolin-6-carboxylate (4.5 g, 34%) as a solid.

TLC, petroleum ether / EtOAc, 8: 2, R _f = 0.6

LC-MS: M / Z ESI: 1.50 min, 223.19 (M + l). ¹ H NMR (DMSO-d6) δ 8.66 (d, J 1.9 Hz, 1H), 8.39 (s, 1H), 8.30 (dd, J = 0.6 Hz, 8.5 Hz, 1H), 7.79 (d, J = 8.5 Hz , 1H), 3.90 (s, 3H).

Intermediate 8: Preparation of 4-methoxy-quinazolin-6-carboxylic acid methyl ester

200 mg of methyl-4-chloroquinoline-6-carboxylate was stirred at 60 ° C. in 5 ml MeOH for 24 h in the presence of DIEA 1 eq. MeOH was evaporated and the crude residue was taken up in EtOAc and washed with NH ₄ Cl to give a white solid sufficiently pure for use in the next step.

HPLC: 2.3 min. LC-MS: M / Z ESI: 1.19 min, 219.17 (M + l).

The following intermediate was synthesized according to the synthesis method of Intermediate 8.

Intermediate 9: Preparation of 4-methylamino-quinazolin-6-carboxylic acid methyl ester

HPLC: 1.12 min. LC-MS: M / Z ESI: 1.06 min, 218.31 (M + l).

Intermediate 10: Preparation of 4-methoxy-quinazolin-6-carbaldehyde

The intermediate was prepared according to the synthesis of Intermediate 5 using 4-methoxy-quinazolin-6-carboxylic acid methyl ester as starting material.

HPLC: 1.41 min. LC-MS: M / Z ESI: 1.24 min, 189.31 (M + l).

Intermediate 11: Preparation of 4-methylamino-quinazolin-6-carbaldehyde

The intermediate was prepared according to the synthesis of Intermediate 5 using 4-methylamino-quinazolin-6-carboxylic acid methyl ester as starting material.

HPLC: 1.3 min. LC-MS: M / Z ESI: 0.90 min, 188.34 (M + l).

Intermediate 12: Preparation of 4-chloro-quinazolin-6-carbaldehyde

Step I: 4-Chloroquinazolin-6-yl Methanol

To a solution of methyl-4-chloroquinazolin-6-carboxylate (3.5 g, 0.015 mol) in dry THF (35 mL) was added DIBAL-H (4.4 g, 0.031 mol) at -25 ° C and at -25 ° C. Stir for 2 hours to room temperature. The reaction mixture was cooled to −10 ° C. and the reaction was terminated with 10% NaHCO ₃ aqueous solution (9 mL). The reaction mixture was extracted with ethyl acetate (100 mL), washed with water, brine and dried. The solvent was removed in vacuo to afford 4-chloroquinolin-6-yl methanol (2 g, 66%).

TLC, chloroform / methanol, 8: 2, R _f = 0.35

Step II: 4-Chloroquinazolin-6-Carboxaldehyde

To a solution of 4-chloroquinazolin-6-yl-methanol (3.5 g, 0.018 mol) in dry CH ₂ Cl ₂ (100 mL) was added Dess-Martin periodinane (8.4 g, 0.019 mol). Add and stir for 30 minutes at room temperature. The reaction mixture was washed with 10% aqueous NaHCO ₃ (75 mL), water, brine and dried. The solvent was removed in vacuo to afford 4-chloroquinazolin-6-carboxaldehyde (3 g, 88%) as a pale yellow solid.

TLC, chloroform / methanol, 9: 1, R _f = 0.6

Intermediate 13: Preparation of 4-phenyl-quinazolin-6-carbaldehyde

4-chloro-quinazolin-6-carbaldehyde (50 mg, 0.26 mmol), Pd (PPh ₃ ) ₄ (13 mg, 0.01 mmol), phenylboronic acid (63 mg, 0.52 mmol) and sodium carbonate (saturated solution: 50 μl) Heated to toluene to 100 ° C. for 12 h. After evaporation of the solvent, the residue was taken up in ethyl acetate and washed twice with brine. The organic phase was concentrated and the crude material was purified on silica gel using DCM / EtOH 95: 5 as eluent to afford 50 mg (82%) of the desired cpd in 85% purity.

HPLC: 2.68 min. LC-MS: M / Z ESI: 1.25 min, 235.30 (M + l).

Intermediate 14: Preparation of 4-dimethylamino-quinazolin-6-carbaldehyde

4-Chloro-quinazolin-6-carbaldehyde (200 mg, 1 mmol) was dissolved in 10 ml dioxane. To this solution was added aqueous dimethylamine solution (5eq). The mixture was stirred at rt for 2 h. The solvent was evaporated and the remaining amine concentrated under high vacuum to give pure 4-dimethylamino-quinazolin-6-carbaldehyde as a yellow solid, which was used in the next step without further purification (190 mg = 91%).

HPLC: 0.91 min. LC-MS: M / Z ESI: 1.23 min, 202.33 (M + l). ¹ H NMR (CDCl ₃ ): δ 10.19 (s, 1H), 8.70 (s, 1H), 8.50 (d, J = 3Hz, 1H), 8.15 (dd, J = 3Hz, 9Hz, 1H), 7.88 (d , J = 9 Hz, 1H).

The following intermediates were synthesized in a similar manner using the appropriate amines as nucleophiles.

No. Intermediate M / Z ESI: (M + 1) 15 4-piperidin-1-yl-quinazolin-6-carbaldehyde 242.27 16 4-amino-quinazolin-6-carbaldehyde 174.18 17 4-benzylamino-quinazolin-6-carbaldehyde 264.30 18 4-[(pyridin-2-ylmethyl) -amino] -quinazolin-6-carbaldehyde 265.33 19 4-[(pyridin-3-ylmethyl) -amino] -quinazolin-6-carbaldehyde 265.33 20 4- (4-Methyl-piperazin-1-yl) -quinazolin-6-carbaldehyde 257.31 21 4-diethylamino-quinazolin-6-carbaldehyde 230.28 22 4-morpholin-4-yl-quinazolin-6-carbaldehyde 244.26 23 1- (6-Formyl-quinazolin-4-yl) -piperidine-3-carboxylic acid ethyl ester 314.36 24 1- (6-formyl-quinazolin-4-yl) -pyrrolidine-2-carboxylic acid tert-butylester 328.39 25 1- (6-Formyl-quinazolin-4-yl) -piperidine-4-carboxylic acid ethyl ester 314.36 26 4- (4-Hydroxy-piperidin-1-yl) -quinazolin-6-carbaldehyde 258.30 27 4- (4-Methyl-piperidin-1-yl) -quinazolin-6-carbaldehyde 256.32 28 4- (4-phenyl-piperidin-1-yl) -quinazolin-6-carbaldehyde 346.42 29 4- (4-benzyl-piperidin-1-yl) -quinazolin-6-carbaldehyde 332.40 30 4- [4- (4-Fluoro-phenyl) -piperidin-1-yl] -quinazolin-6-carbaldehyde 336.38 31 4- (4-Pyrimidin-2-yl-piperazin-1-yl) -quinazolin-6-carbaldehyde 321.36

Intermediate 32: Preparation of Methyl-benzotriazole-5-carboxylic Acid Methyl Ester

1 g (5.64 mmol) of benzotriazole-5-carboxylic acid methyl ester was dissolved in 20 ml of DMF at 0 ° C. To this solution was added NaH (60%) 1eq at 0 ° C. The mixture was stirred at 0 ° C. for 30 minutes, 801 mg (1 eq.) Methyl iodide was slowly added and the resulting reaction mixture was stirred at room temperature for 2 hours. EtOAc was added and the organic layer was washed extensively with brine and water, dried over MgSO ₄ and filtered to give 1 g of crude methyl-benzotriazole-5-carboxylic acid methyl ester as three different regioisomers. Separation was performed on silica gel using EtOAc / CH 3: 7 as eluent.

Intermediate 32a: 2-methyl-2H-benzotriazole-5-carboxylic acid methyl ester

2-Methyl-2H-benzotriazole-5-carboxylic acid methyl ester eluted with the first fraction (250 mg, 22%). HPLC: 2.32 min. ¹ H NMR (DMSO-d6) δ 8.56 (s, 1H), 8.02 (d, J = 9 Hz, 1H), 7.93 (d, J = 9 Hz, 1H), 4.55 (s, 3H), 3.90 (s, 1H).

Intermediate 32b: 3-methyl-3H-benzotriazole-5-carboxylic acid methyl ester

3-Methyl-3H-benzotriazole-5-carboxylic acid methyl ester eluted with the second fraction (130 mg, 12%). HPLC: 2.03 min. ¹ H NMR (DMSO-d6) δ 8.56 (s, 1H), 8.13 (d, J = 6 Hz, 1H), 7.93 (d, J = 9 Hz, 1H), 4.39 (s, 3H), 3.92 (s, 3H).

Intermediate 32c: 1-methyl-1H-benzotriazole-5-carboxylic acid methyl ester

1-methyl-1H-benzotriazole-5-carboxylic acid methyl ester eluted with the third fraction (135 mg, 12%). HPLC: 2.03 min. ¹ H NMR (DMSO-d6) δ8.62 (s, 1H), 8.11 (d, J = 9Hz, 1H), 7.97 (d, 9Hz, 1H), 4.35 (s, 3H), 3.90 (s, 3H) .

Intermediate 33: 2-Methyl-2H-benzotriazole-5-carbaldehyde

The intermediate was synthesized according to the synthesis method of Intermediate 5 using 2-methyl-2H-benzotriazole-5-carboxylic acid methyl (intermediate 32a) as starting material.

HPLC: 1.88 min. ¹ H NMR (DMSO-d6) δ 10.12 (s, 1H), 8.65 (s, 1H), 8.06 (d, J = 9 Hz, 1H), 7.85 (d, J = 9 Hz, 1H), 4.57 (s, 3H ).

Intermediate 34: 3-Methyl-3H-benzotriazole-5-carbaldehyde

The intermediate was synthesized according to the synthesis of Intermediate 5 using 3-methyl-3H-benzotriazole-5-carboxylic acid methyl ester (intermediate 32b) as starting material.

HPLC: 1.49 min. ¹ H NMR (DMSO-d6) δ 10.18 (s, 1H), 8.54 (s, 1H), 8.20 (d, J = 9 Hz, 1H), 7.88 (d, J = 9 Hz, 1H), 4.41 (s, 3H ).

Intermediate 35: 1-Methyl-1H-benzotriazole-5-carbaldehyde

The intermediate was synthesized according to the synthesis method of Intermediate 5 using 1-methyl-1H-benzotriazole-5-carboxylic acid methyl ester (intermediate 32c) as starting material.

HPLC: 1.49 min. LC-MS: M / Z ESI: 1.07 min, 162.32 (M + l). ¹ H NMR (DMSO-d 6) δ 10.13 (s, 1H), 8.70 (s, 1H), 8.05 (s, 2H), 4.36 (s, 3H).

Intermediate 36: 5- (4-Amino-3-ethylamino-benzylidene) -thiazolidine-2,4-dione

Step I: 3-fluoro 4-nitrobenzyl alcohol ( Bioorg. Med. Chem. 7 , 1999, 2647)

To an ice cold suspension of NaBH ₄ (204 mg, 5.4 mmol, 2eq.) In THF (10 mL) was added dropwise 3-fluoro 4-nitro benzoic acid (500 mg, 2.7 mmol, 1 eq.) In THF (10 mL) over 30 minutes. Then BF ₃ -Et ₂ O (7.3 mmol, 2.7 eq.) Was added dropwise over 30 minutes. The solution was stirred overnight at room temperature. 1N HCl was added dropwise to terminate the extra NaBH ₄ reaction. The solvent was removed in vacuo and the residue was dissolved in DCM and washed with water and brine. The organic layer was dried over MgSO ₄ and the solvent removed in vacuo to yield 425 mg of 3-fluoro 4-nitrobenzyl alcohol (92% yield). The compound was used in the next step without further purification.

¹ H NMR: δ = (400 MHz, CDCl ₃ ): 7.97 (m, 1H), 7.28 (m, 1H), 7.18 (m, 1H), 4.75 (m, 2H).

Step II: 3-fluoro 4-nitrobenzyl aldehyde

3-fluoro 4-nitrobenzyl alcohol (116 mg, 0.68 mmol, 1 eq.) Was dissolved in DCM (10 ml), treated with MnO ₂ (580 mg, 6.73 mmol, 10 eq.) And the suspension was stirred at rt overnight. The suspension was filtered using celite to remove MnO ₂ and the solvent was evaporated to give the corresponding aldehyde as a white solid (66% yield).

¹ H NMR: δ = (400 MHz, CDCl ₃ ): 9.98 (s, 1H, CHO), 8.08 (m, 1H, ArH), 7.78 (m, 2H, ArH).

Step III: 5- (3-Fluoro-4-nitro-benzylidene) -thiazolidine-2,4-dione ( J. Med. Chem.  37, 2, 1994, 322)

3-fluoro-4-nitrobenzyl aldehyde (280 mg, 1.65 mmol, 1 eq.), Thiazolidine-dione (193 mg, 1.65 mmol, 1 eq.) And β-alanine (95 mg, 1.1 mmol, 0.65 in acetic acid (5 mL) eq.) was stirred at 100 ° C. overnight. The cooled reaction mixture was added to water and stirred for 1 hour. The precipitated product was filtered off, washed with water and dried to give the final compound as a yellow / orange solid (77% yield).

1 H NMR: δ = (400 MHz, (CD ₃ ) ₂ CO): 8.0 (m, 1H, ArH), 7.68 (m, 2H, ArH), 7.53 (s, 1H, CH = C).

Step IV: 5- (3-Ethylamino-4-nitro-benzylidene) -thiazolidine-2,4-dione

5- (3-Fluoro-4-nitro-benzylidene) -thiazolidine-2,4-dione (200 mg, 0.75 mmol, 1 eq.) Was added to DME (6 mL) and TEA (208 μL, 1.5 mmol, 2 eq. ) And a solution of ethylamine (2eq.) Was added. The reaction mixture was shaken at 60 ° C. overnight. The solvent was removed in vacuo and the residue was dissolved in ethyl acetate and washed with 10% aqueous ammonium chloride solution. The organic layer was dried over Na ₂ SO ₄ and the solvent was evaporated to yield the corresponding aniline derivative as a red oil which was used in the next step without further purification.

Step V: 5- (3-ethylamino-4-amino-benzylidene) -thiazolidine-2,4-dione

To a stirred solution of 5- (3-ethylamino-4-nitro-benzylidene) -thiazolidine-2,4-dione in THF, aqueous sodium hydrosulfite solution (3eq.) Was slowly added, followed by K ₂ CO ₃ aqueous solution was added. The reaction mixture was refluxed overnight. THF was removed in vacuo and the residue was extracted with ethyl acetate. The organic layer was dried over Na ₂ S0 ₄ and the solvent was evaporated to yield the corresponding aniline derivative and used without further purification.

The following intermediates were synthesized in a similar manner using appropriate amines as nucleophiles as described in step IV of intermediate 36. 3-alkylamino-4-nitro-benzylidene) -thiazolidine-2,4-dione thus obtained is reduced as described in step V of intermediate 36 to 3-alkylamino-4-amino-benzylidene) -Tazolidine-2,4-dione was obtained.

No. Intermediate M / Z ESI: (M + 1) 37 5- [4-Amino-3- (4-phenyl-butylamino) -benzylidene] -thiazolidine-2,4-dione 368.2 38 5- {4-Amino-3- [2- (4-trifluoromethyl-phenyl) -ethylamino] -benzylidene} -thiazolidine-2,4-dione 408.12 39 5- {4-Amino-3- [2- (4-hydroxy-phenyl) -ethylamino] -benzylidene} -thiazolidine-2,4-dione 356.13 40 4- [2-Amino-5- (2, 4-dioxo-thiazolidine-5-ylidenemethyl) -phenylamino] -cyclohexanecarboxylic acid methyl ester 376.35 41 5- {4-Amino-3- [2- (1H-indol-3-yl) -ethylamino] -benzylidene} -thiazolidine-2,4-dione 409.21 42 5- {4-amino-3-[(1-methyl-1H-pyrazol-4-ylmethyl) -amino] -benzylidene} -thiazolidine-2,4-dione 331.1 43 5- {4-Amino-3- [2- (3,4-dimethoxy-phenyl) -ethylamino] -benzylidene-thiazolidine-2,4-dione 400.21 44 5- [4-Amino-3- (4-trifluoromethyl-benzylamino) -benzylidene} -thiazolidine-2,4-dione 394.15 45 4- [2-Amino-5- (2, 4-dioxo-thiazolidine-5-ylidenemethyl) -phenylamino] -cyclohexanecarboxylic acid 362.17 46 5- (4-Amino-3-isobutylamino-benzylidene) -thiazolidine-2,4-dione 292.22 47 5- [4-Amino-3- (2-benzo [l, 3] dioxol-4-yl-ethylamino) -benzylidene] -thiazolidine-2,4-dione 384.26 48 5- {4-Amino-3- [2- (2-phenoxy-phenyl) -ethylamino] -benzylidene} -thiazolidine-2,4-dione 432.28 49 5- [4-Amino-3- (3,3-diphenyl-propylamino) -benzylidene] -thiazolidine-2,4-dione 430.27 50 5- (4-Amino-3-prop-2-ylamino-benzylidene) -thiazolidine-2,4-dione 274.21 51 5- [4-Amino-3- (2-methoxy-benzylamino) -benzylidene] -thiazolidine-2,4-dione 356.23 52 5- {4-Amino-3-[(furan-3-ylmethyl) -amino] -benzylidene} -thiazolidine-2,4-dione 316.21 53 5- (4-Amino-3-propylamino-benzylidene) -thiazolidine-2,4-dione 278.16 54 5- {4-Amino-3- [2- (4-phenoxy-phenyl) -ethylamino] -benzylidene} -thiazolidine-2,4-dione 432.23

Intermediate 55: Quinoxaline-6-carbaldehyde

Step I: Quinoxaline-6-carbonyl chloride

Into a 1 L three neck flask was placed quinoxaline-6-carboxylic acid (20.2 g) in 500 ml of THF. Thionyl chloride (42 ml, 5eq.) Was slowly added to this solution. The stirred reaction was allowed to warm to reflux and the sample was quenched with NH ₄ OH. After 3 hours at reflux no further starting material was present, the solvent was removed under reduced pressure and the SOCl ₂ was driven three times with toluene. The solid was suspended in 100 ml EtOAc and filtered to give 23.47 g of beige solid.

HPLC: 1.114 min. ¹ H NMR (DMSO-d 6) δ 9.01-7.40 (m, 5H).

Step I: Quinoxaline-6-carbaldehyde

Into a 1 L 3-necked flask under argon was placed quinoxaline-6-carbonyl chloride in 600 ml of DME. Lithium tri-tert-butoxyaluminohydride (1eq.) Was added to this solution at -78 ° C over 1.5 hours. The reaction was kept at this temperature for 5 hours. Then ice was added and the reaction diluted with AcOEt and filtered over celite. The two layers were separated and the organic phase was washed with saturated NaHCO ₃ . The solvent was evaporated to give quinoxaline-6-carbaldehyde as a yellow solid in 73% yield.

HPLC: 1.49 min. LC-MS: M / Z ESI: 0.81 min, 159.37 (M + l). ¹ H NMR (CDCl ₃ ) δ 10.28 (s, 1H), 8.97 (s, 2H), 8.61 (s, 1H), 8.27 (q, 6Hz, 9Hz, 2H).

Intermediate 56: Benzothiazole-6-carbaldehyde

The intermediate was synthesized according to the synthesis method of Intermediate 55 using benzothiazole-6-carboxylic acid as the starting material. Overall yield was 38%.

HPLC: 1.92 min. LC-MS: M / Z ESI: 0.97 min, 164.27 (M + l). ¹ H NMR (DMSO-d 6) δ 10.1 (s, 1H), 9.60 (s, 1H), 8.60 (s, 1H), 8.20 (m, 1H), 8.10 (d, 1H).

Intermediate 57: 3-Methyl-benzofuran-5-carbaldehyde

The intermediate was obtained by the same route as Intermediate 1 using ethyl-2-acetyl-4-bromophenoxy acetate as starting material. Overall yield was 50%.

LC-MS: M / Z ESI: 1.55 min, 161.34 (M + l). ¹ H NMR (DMSO-d6) δ 10.1 (s, 1H), 8.21 (d, J = 1.5 Hz, 1H), 7.92 (d, J = 1.3 Hz, 1H), 7.88-7.84 (dd, J = 1.6 Hz , 1H), 7.73-7.71 (d, J = 8.5 Hz, 1H), 2.25 (s, 3H).

Intermediate 58: 3-Bromo-benzofuran-5-carbaldehyde

Step I: 2,3-Dibromo-2,3-dihydro-benzofuran-5-carbaldehyde

Intermediate 1 (2 g, 13.7 mmol) was dissolved in 10 ml CHCl ₃ and cooled to -10 ° C. To this was added a Br ₂ solution in CHCl ₃ (1.55 eq., C = 4.162 mol / l). The reaction mixture turned brown and was allowed to reach room temperature for 1 hour. HPLC confirmed complete addition of bromine. The solvent and the remaining bromine were evaporated under reduced pressure to give a reddish oil (4.1 g = 90%) which was used in the next step without further purification.

HPLC: 3.43 min

Step II: 3-Bromo-1-benzofuran-5-carbaldehyde

To a solution of 2,3-dibromo-2,3-dihydro-1-benzofuran-5-carbaldehyde (4.1 g) in dry ethanol (15 mL) of KOH (2.2 eq.) In dry ethanol (14 mL) The solution was added and refluxed at 70 ° C. for 1 hour. The reaction mixture was cooled down, diluted with water and extracted with EtOAc (3x50 mL). The organic layer was washed with water and brine and dried. The solvent was removed in vacuo and the residue was purified by flash chromatography (petroleum ether / EtOAc 99.5: 0.5) to afford the title compound as a pale yellow solid (2.91 g (80% purity), yield = 78%).

HPLC: 3.35 min. ¹ H NMR (DMSO-d6, 300 MHz) δ 10.12 (s, 1H), 8.47 (s, 1H), 8.14 (d, J = 1.5 Hz, 1H), 7.97 (dd, J = 8.6, 1.5 Hz, 1H ), 7.87 (d, J = 8.6 Hz, 1H).

Intermediate 59: 3-phenylethynyl-benzofuran-5-carbaldehyde

3-bromo-1-benzofuran-5-carbaldehyde (1 g, 4.4 mmol) was dissolved in dry THF (50 ml) in a dry flask. To this was added bis (triphenylphosphine) palladium (II) chloride (160 mg, 0.2 mmol), TEA (2.81 mL, 5eq.), CuI (40 mg, 0.2 mmol) and phenylacetyline (897 mg, 8.8 mmol) under argon. Added. The reaction was heated to 55 ° C. for 2 days. The crude was filtered through celite and purified on silica gel using cyclohexane-ethyl acetate (7-3) as eluent to afford 680 mg (yield: 56%).                 

HPLC: 4.71 min. ¹ H NMR (DMSO-d6) δ 10.14 (s, 1H), 8.64 (s, 1H), 8.38 (s, 1H), 7.97 (dd, J = 1.5HZ, 8.3 Hz, 1H), 7.90 (d, J = 8.6 Hz, 1H), 7.65 (m, 2H), 7.46 (m, 3H).

Intermediate 60: 3- (5-formyl-benzofuran-3-yl) -acrylic acid ethyl ester

3-bromo-1-benzofuran-5-carbaldehyde (500 mg, 2.22 mmol) was dissolved in 7 ml of ACN in a sealed tube. To this solution was added PPh ₃ (1.16 g, 4.44 mmol), Pd (II) acetate (500 mg, 2.2 mmol), Et ₃ N (073 mL, 5.55 mmol), and finally acrylic acid ethyl ester (2.41 ml, 22 mmol). It was. The tube was sealed and the reaction heated to 120 ° C. for 1 hour. The crude was filtered over celite and the inorganic contaminants were removed. The solvent was evaporated and the crude was purified by silica gel chromatography using cyclohexane-AcOEt 95-5 to 50-50. A pale yellow solid was obtained (400 mg, yield: 42%).

HPLC: 3.69 min. ¹ H NMR (DMSO-d6) δ 10.15 (s, 1H), 8.70 (s, 2H), 7.97 (d, J = 9 Hz, 1H), 7.88 (s, 1H), 7.82 (s, 1H), 6.76 ( d, J = 15 Hz, 1 H), 4.23 (q, J = 6 Hz, 12 Hz, 2H), 1.28 (t, J = 9 Hz, 3H).

Intermediate 61: 2,3-dihydro-benzo [1,4] oxazine-4,6-dicarboxylic acid 4-tert-butyl ester 6-methyl ester

Step I: 3-Amino-4-hydroxy-benzoic acid methyl ester

To a 2000 ml 3-necked flask containing 3-nitro-4-hydroxy-benzoic acid methyl ester (43 g, 218 mmol) in MeOH (860 ml; 20 vols) was added palladium on carbon in water (2 g in 10 ml of water). Ammonium formate (68.76 g, 5eq.) Was added in one portion with stirring. After 2-3 minutes the suspension was observed and the temperature was raised from 20 ° C to 30 ° C. The reaction mixture was cooled to 20 ° C. using an ice bath and the reaction was stirred at 20 ° C. for 40 minutes until the reaction was complete (no yellow color). The reaction mixture was filtered over a silica plug, washed with MeOH and the filtrate was concentrated in vacuo to give a green oil which was taken up in ethyl acetate (400 ml). The organic phase was washed twice with water, dried over MgSO ₄ , filtered and concentrated to give a creamy solid m = 31.35 g (86%),

LC-MS: M / Z ESI: 0.81 min, 168.37 (M + 1)

Step II: 3,4-Dihydro-2H-benzo [1,4] oxazine-6-carboxylic acid methyl ester * hydrochloric acid

K ₂ CO ₃ (103 g, 4eq.) Was added to a 2000 ml 3-necked flask under nitrogen containing 3-amino-4-hydroxy-benzoic acid methyl ester (31.35 g, 187 mmol) in anhydrous DMF (630 ml; 20 vols) at room temperature. After addition in one portion, 1,2-dibromoethane (65 ml, 4eq.) Was added in one portion. The reaction mixture was stirred at 70 ° C. for 12 h. The temperature was cooled to room temperature and HCl 1N was added to pH = 8 and extracted using diethyl ether (3 * 200 ml). The organic phase was washed with water (2 * 200 ml), dried over MgSO ₄ and concentrated to give a reddish brown oil with solid which was again dissolved in diethyl ether (450 ml) and THF (50 ml) and filtered to remove white solid. HCl 1N was added to the filtrate, diethyl ether (130 ml) was added and the suspension was stirred at rt for 5 min and filtered to give 27.6 g of crude product. The aqueous phase was extracted again with ethyl acetate to give an additional 6.23 g of product. The mixed fractions (32 g) were recrystallized in EtOH, filtered and dried to give a white powder (19.47 g (16.37 g debase)), yield = 40%.

HPLC: 1.954 min. LC-MS: M / Z ESI: 1.27 min, 194.45 (M + l).

Step II: 2,3-Dihydro-benzo [1,4] oxazine-4,6-dicarboxylic acid 4-tert-butyl ester 6-methyl ester

In a 500 ml 3-necked flask containing 3,4-dihydro-2H-benzo [1,4] oxazine-6-carboxylic acid methyl ester * hydrochloric acid in a suspension in THF (145 ml; 10 vols) under N ₂ DIEA (27 ml, 2.5eq.) Was added in one portion at room temperature and partial solubilization was observed. Boc anhydride / (16.4 g, 1.2eq.) Was added in one portion and the reaction stirred at 65 ° C. for 5 days. During that time DIEA and Boc ₂ O 0.2 eq. Were added in small portions. THF was removed under vacuum and the residue was taken up in 150 ml of DCM. The organic phase was washed with saturated NaHCO ₃ solution followed by brine. After drying over MgSO ₄ and filtration, the volatiles were removed in vacuo and the residue was recrystallized in EtOH (80 ml) to give cream colored crystals (14.8 g, 76%).

HPLC: 4.038 min. ¹ H NMR (CDCl ₃ ) δ 8.49 (s, 1H), 7.68 (dd, J = 3Hz, 9Hz, 1H), 6.89 (d, J = 9Hz, 1H), 4.30 (Q, J = 3Hz, 9Hz, 2H ), 3.89 (m, 5H), 1.62 (s, 9H).

Intermediate 62: 6-formyl-2,3-dihydro-benzo [1,4] oxazine-4-carboxylic acid tert-butyl ester

The intermediate was obtained via oxidation-reduction as described in intermediate 5.

HPLC: 3.727 min. LC-MS: M / Z ESI: 1.81 min, 264.34 (M + l). ¹ H NMR (DMSO-d6) δ 9.83 (s, 1H), 8.35 (s, 1H), 7.53 (d, J = 6 Hz, 1H), 7.05 (d, J = 9 Hz, 1H), 4.31 (t, J = 3 Hz, 2H), 3.83 (t, J = 6 Hz, 2H), 1.50 (s, 9H).

Intermediate 63: 6-formyl-benzo [1,4] oxazine-4-carboxylic acid tert-butyl ester

Step I: 2,3-Dibromo-2,3-dihydro-benzo [1,4] oxazine-4,6-dicarboxylic acid 4-tert-butyl ester 6-methyl ester

N in a solution of 2,3-dihydroxy-benzo [1,4] oxazine-4,6-dicarboxylic acid 4-tert-butyl ester 6-methyl ester (500 mg, 1.7 mmol) in dry carbon tetrachloride (20 ml) Bromosuccinimide (667 mg, 3.75 mmol) and catalytic amount of benzoylperoxide were added. The resulting mixture was stirred and heated to reflux with a bulb lamp (100 W) for 45 minutes. The mixture was cooled and succinimide was removed by filtration. The filtrate was evaporated to give an oil (767 mg, 99%) pure enough to be used for the next step.

HPLC: 3.978 min

Step II: Benzo [1,4] oxazine-4,6-dicarboxylic acid 4-tert-butyl ester 6-methyl ester

2,3-dibromo-2,3-dihydro-benzo [1,4] oxazine-4,6-dicarboxylic acid 4-tert-butyl ester 6-methyl ester (767 mg, 1.7 mmol) obtained in the previous step Was stirred with NaI (1.27 g, 8.5 mmol) in acetone (14 ml) at room temperature for 2 hours. Solvent was removed and EtOAc, water and 1M sodium thiosulfate were added. After separating the phases, the organic layer was washed with brine. The solvent was concentrated and the crude was purified on silica gel using CH / EtOAc 7: 3 to give a colorless oil (456 mg, 92%).

HPLC: 4.386 min

Step III: 6-hydroxymethyl-benzo [1,4] oxazine-4-carboxylic acid tert-butyl ester

Step IV: 6-formyl-benzo [1,4] oxazine-4-carboxylic acid tert-butyl ester

Steps III and IV were carried out according to the synthesis of intermediate 5.

HPLC: 3.388 min

Intermediate 64: (6-formyl-3-oxo-2,3-dihydro-benzo [1,4] oxazin-4-yl) -acetic acid methyl ester

Step I: Methyl-3-amino-4-hydroxybenzoate

Thionyl chloride (233 g, 1.96 mol) was added dropwise at 5-10 DEG C while stirring a solution of 3-amino-4-hydroxybenzoic acid (100 g, 0.65 mol) in methanol (1.5 L) and refluxed at 65 DEG C for 16 hours. I was. Excess methanol and thionyl chloride were distilled off and the crude was dissolved in ethyl acetate (500 mL). The organic layer was washed with 5% NaHCO ₃ aqueous solution, water, brine and dried. The solvent was removed in vacuo to afford methyl-3-amino-4-hydroxybenzoate (105 g, 95%).

Step II: Methyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-6-carboxylate

NaHCO ₃ (211 g, 2.5 mol) while stirring a mixture of methyl-3-amino-4-hydroxybenzoate (105 g, 0.62 mol) and benzyltriethylammonium chloride (142 g, 0.62 mol) in dry CHCl ₃ (1.5 L) ) Was added. The reaction mixture was cooled to −5 ° C. and chloroacetylchloride (85 g, 0.75 mol) in dry CHCl ₃ (350 mL) was added over 1.5 hours at the same temperature. The reaction mixture was then heated to 55 ° C. for 16 hours. The solvent was removed in vacuo, water (3 L) was added and the solid was filtered off. The solid product was dried and recrystallized in ethanol to afford methyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-6-carboxylate (108 g, 83%).

Step III: 6- (hydroxymethyl) -2H-1,4-benzoxazin-3 (4H) -one

Cool a solution of methyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-6-carboxylate (30 g, 0.145 mol) in dry CH ₂ Cl ₂ (500 mL) to -78 ° C. DIBAL-H (51 g, 0.36 mol) was added over 45 minutes and stirred at the same temperature for 14 hours. The reaction mixture was quenched with 1.5N HCl and the solid product was filtered off. The solid compound was dried under vacuum to afford 6- (hydroxymethyl) -2H-1,4-benzoxazin-3 (4H) -one (18 g, 69%).

Step IV: TBDMS-6- (hydroxymethyl) -2H-1,4-benzoxazin-3 (4H) -one

Add imidazole (13.7 g, 0.2 mol) to a solution of 6- (hydroxymethyl) -2H-1,4-benzoxazin-3 (4H) -one (18 g, 0.1 mol) in dry DMF (250 mL). And stirred at 0 ℃ for 30 minutes. TBDMSiCl (23 g, 0.15 mol) was added in portions to the reaction mixture and stirred at room temperature for 4 hours. The reaction mixture was distilled with water and the solid obtained was filtered off. The solid was dried under vacuum to afford TBDMS-6- (hydroxymethyl) -2H-1,4-benzoxazin-3 (4H) -one (24.5 g, 83%).

Step V: Methyl- [6- (hydroxymethyl) -3-oxo-2,3-dihydro-4H-1,4-benzoxazin-4-yl] acetate

TBDMS-6- (hydroxymethyl) -2H-1,4-benzoxazin-3 (4H) -one (2 g) at 0 ° C. with stirring a suspension of NaH (0.3 g, 0.01 mol) in dry DMF (15 mL). , 0.0068 mol) was added and stirred at room temperature for 2 hours. The reaction mixture was cooled to 0 ° C., methylchloroacetate (1 g, 0.0088 mol) was added and stirred at room temperature for 12 hours. The reaction mixture was cooled back to 0 ° C., 50 mL of 1.5N HCl solution was added and stirred at rt for 12 h. The reaction mixture was distilled with water (200 mL) and extracted with ethyl acetate (3x150 mL). The combined organic layers were washed with 10% aqueous NaHCO ₃ , brine and dried. The solvent was removed in vacuo and the crude was purified by column chromatography on silica gel (CHCl ₃ / methanol, 99.5: 0.5) to give methyl- [6- (hydroxymethyl) -3-oxo-2,3-dihydro-4H -1,4- [benzoxazin-4-yl] acetate was obtained (1.2 g, 70%).

Step VI: Methyl- [6- (formyl) -3-oxo-2,3-dihydro-4H-1,4-benzoxazin-4-yl] acetate

A mixture of PCC (4.2 g, 0.019 mol) and celite (4 g) in dry CH ₂ Cl ₂ (100 mL) was cooled to 0 ° C. and methyl- [6- (hydroxymethyl in CH ₂ Cl ₂ (30 mL) under nitrogen. A solution of) -3-oxo-2,3-dihydro-4H-1,4-benzoxazin-4-yl] acetate was added slowly. The reaction mixture was stirred at rt for 2 h, passed through celite, washed with CH ₂ Cl ₂ (50 mL) and concentrated to afford crude product, which was purified on silica gel to give 1.05 g (87%).

LC-MS: M / Z ESI: 1.15 min, 250.41 (M + l). ¹ H NMR (DMSO-d6) δ 9.88 (s, 1H), 7.65-7.60 (m, 2H), 7.24 (d, J = 8.1 Hz, 1H), 4.85 (d, J = 9.9 Hz, 4H), 3.71 (s, 3 H).

Intermediate 65: 4-Butyl-3-oxo-3,4-dihydro-2H-benzo [1,4] oxazine-6-carbaldehyde

The intermediate was synthesized according to the synthesis method of intermediate 2. Overall yield 33%.                 

LC-MS: M / Z ESI: 1.60 min, 234.35 (M + l). ¹ H NMR (DMSO-d6) δ 7.66 (d, J = 0.7 Hz, 1H), 7.58 (dd, J = 1.7 Hz, 8.1 Hz, 1H), 7.18 (d, J = 8.2 Hz, 1H), 4.77 (s, 2H), 3.96 (t, J = 7.3 Hz, 1H), 1.61-1.51 (m, 3H), 1.97-1.27 (m, 3H), 0.91 (t, J = 7.3 Hz, 3H).

Intermediate 66: 4-benzyl-3-oxo-3,4-dihydro-2H-benzo [1,4] oxazine-6-carbaldehyde

The intermediate was synthesized according to the synthesis method of intermediate 2. Overall yield 29%.

¹ H NMR (DMSO-d6) δ 9.78 (s, 1H), 7.58 (dd, J = 1.5 Hz, 7.9 Hz, 1H), 7.47 (d, J = 1.9 Hz, 7.40-7.18 (m, 6H), 5.22 (s, 2H), 4.95 (s, 2H), 3.3 (d, J = 7.2 Hz, 1H).

Step 67: 2-Chloro-5- [1,3] dioxolan-2-yl-benzofuran

Step I: 5- [1,3] dioxolan-2-yl-benzofuran

Of benzofuran-5-carbaldehyde (150 mg, 1.03 mmol), ethylene glycol (230 μl, 4eq.), Trimethyl orthoformate (123 μl, 1.1eq.) And tetrabutylammonium tribromide (49 mg, 0.1eq.) The mixture was stirred at rt overnight. Some starting material can be detected by TLC. However, the reaction mixture was poured into saturated NaHCO ₃ solution and the product extracted with ethyl acetate. The organic layers were combined, dried over anhydrous sulfate, filtered and concentrated to afford crude product, which was purified by flash chromatography using cyclohexane / ethyl acetate 20: 0.75 as eluent. The title compound was obtained in 36% yield (70 mg).

LC-MS: M / Z ESI: 1.51 min, 191.30 (M + l).

Step II: 2-Chloro-5- [1,3] dioxolan-2-yl-benzofuran

5- [1,3] dioxolan-2-yl-benzofuran (50 mg, 0.26 mmol) was dissolved in THF (2 mL) and the solution was cooled to -78 ° C. Butyl lithium (180 mu L, 1.1 eq.) Was added dropwise. The mixture was stirred at 25 ° C. for 30 minutes. The reaction mixture was then cooled to −78 ° C. and NCS (39 mg, 1.1 eq.) Dissolved in 1 mL THF was added dropwise to the reaction mixture. After 1 hour 30 minutes at −78 ° C., only a small amount of starting material was detected. The temperature was slowly raised to room temperature overnight. Water and ethyl acetate were added to the mixture, and the aqueous layer was extracted three times. The combined organic phases were dried over MgSO ₄ , filtered and evaporated to afford 2-chloro-5- [1,3] dioxolan-2-yl-benzofuran (48.1 mg, 81%) pure enough to be used in the next step. Obtained.

LC-MS: M / Z ESI: 1.77 min, 225.23 (M + l).

Intermediate 68: 3-amino-benzo [d] isoxazole-5-carbaldehyde

Kaiser oxime resin (Novabiochem 01-64-0188) (250 mg) was washed with DCM and THF (3 times for 5 minutes), 2 ml of THF was added followed by 300 μl potassium tert-butoxide (1M in THF, 1.2eq.) Was added at room temperature. The resin turned orange and was shaken in Quest210 ™ for 15 '. 2-Fluoro-5-formyl-benzonitrile (75 mg, 2eq.) In 1 ml THF was added and the reaction was heated at 55 ° C. for 12 hours. The resin was washed with DCM, MeOH, water (2x5 min each) and MeOH (4x5 min). The resin was dried at 40 ° C. for 30 ′ under argon atmosphere before cleavage.                 

This dried resin was treated with TFA / 5N HCl 4: 1 (2.5 ml) at 55 ° C. for 2 hours. The solution was collected in 20 ml vials and the resin washed twice with 4 ml DCM. Collected fractions were evaporated with Genevac HT4 to yield 37 mg (92%) of pure 3-amino-benzo [d] isoxazole-5-carbaldehyde in dry condition.

HPLC: 1.47 min. LC-MS: M / Z ESI: 0.82 min, 163.26 (M + l).

Intermediate 69: 4-piperidin-1-yl-quinazolin-6-carboxylic acid methyl ester

The intermediate was prepared according to the synthesis method of Intermediate 8 using 4-chloro-quinazolin-6-carboxylic acid methyl ester (Intermediate 7) as a starting material.

HPLC: 1. 81 min. LC-MS: M / Z ESI: 1.78 min, 272.32 (M + l).

Intermediate 70: 4-piperidin-1-yl-quinazolin-6-carbaldehyde

The intermediate was prepared according to the synthesis method of Intermediate 5 using 4-piperidine-quinazolin-6-carboxylic acid methyl ester (Intermediate 71) as a starting material.

HPLC: 1.36 min. LC-MS: M / Z ESI: 1.40 min, 242.32 (M + l).

Intermediate 71: 3- (5-formyl-benzofuran-3-yl) -propionic acid ethyl ester

100 mg of 3- (5-formyl-benzofuran-3-yl) -acrylic acid ethyl ester (intermediate 62) was dissolved in EtOAc in the presence of palladium and argon on charcoal. An H ₂ balloon was connected thereto, and hydrogenation was performed for 12 hours. Palladium was filtered off and the solvent was evaporated to give the pure title compound (80 mg, 80%).

HPLC: 3.53 min. LC-MS: M / Z ESI: 1.68 min, 247.25 (M + l).

Intermediate 72: 2-Methyl-5- [1,3] dioxolan-2-yl-benzofuran

5- [1,3] dioxolan-2-yl-benzofuran (50 mg, 0.26 mmol) was dissolved in THF (2 mL) and the solution was cooled to -78 ° C. Butyl lithium (180 mu L, 1.1 eq.) Was added dropwise. The mixture was stirred at 25 ° C. for 30 minutes. The reaction mixture was then cooled to −78 ° C. and methane iodide (18.1 μl, 1.1 eq.) Dissolved in 1 mL THF was added dropwise to the reaction mixture. The temperature was slowly increased to room temperature overnight. To detect if some starting material was detected, water and ethyl acetate were added to the mixture and the aqueous layer was extracted three times. The combined organic phases were dried over MgSO ₄ , filtered and evaporated to afford 2-methyl-5- [1,3] dioxolan-2-yl-benzofuran (41.2 mg, 70%) pure enough to be used in the next step. Obtained.

LC-MS: M / Z ESI: 1.71 min, 205.34 (M + l).

Intermediate 73: 5- [1,3] dioxolan-2-yl-benzofuran-2-carboxylic acid methyl ester

5- [1,3] dioxolan-2-yl-benzofuran (50 mg, 0.26 mmol) was dissolved in THF (2 mL) and the solution was cooled to -78 ° C. Butyl lithium (180 mu L, 1.1 eq.) Was added dropwise. The mixture was stirred at 25 ° C. for 30 minutes. The reaction mixture was then cooled to −78 ° C. and methyl cyanoformate (23 μl, 1.1 eq.) Dissolved in 1 mL THF was added dropwise to the reaction mixture. After 1 hour 30 minutes only a small amount of starting material was detected and two main compounds were formed (expected product / dimer 73:27). The temperature was slowly raised to room temperature overnight. Water and ethyl acetate were added to the mixture, and the aqueous layer was extracted three times. The combined organic phases were dried over MgSO ₄ , filtered and evaporated to afford 5- [1,3] dioxolan-2-yl-benzofuran-2-carboxylic acid methyl ester (31.9 mg, 44%) mixed with dimer. (Expected product / dimer 46:54). The mixture was used directly in the next step.

LC-MS: M / Z ESI: 1.54 min, 249.26 (M + 1) and 1.88 min, 407.20 (M + 1, dimer).

Intermediate 74: 3-Bromo-2-fluoro-benzofuran-5-carbaldehyde

Benzofuran-5- in ether (1 mL) in a cold solution (-78 ° C.) of 70% (0.850 mL) of pyridinium poly (hydrogen fluoride) in ether (4 mL) and NBS (158 mg, 1.3 eq.) In a polypropylene tube. Carbaldehyde (100 mg, 0.68 mmol) was added. The reaction was allowed to warm to room temperature overnight. The reaction mixture was poured into iced water and extracted with ether. The ether phase was washed with aqueous bicarbonate solution, dried over sodium sulfate, filtered and evaporated to afford 3-bromo-2-fluoro-benzofuran-5-carbaldehyde (141.6 mg). Purification by reverse phase HPLC (solvent gradient H ₂ O / CH ₃ CN 0.1% TFA) afforded the title compound (62 mg, 37%) and used in the next step.

LC-MS: M / Z ESI: 1.56 min. HPLC = 3.11 min (99.34%). ¹ H NMR: (DMSOd6) δ9.94 (s, 1H), 8.09 (d, 1H, ³ J = 1.8 Hz), 7.99 (dd, 1H, ³ J = 8.4, 1.8 Hz), 7.38 (d, 1H, ³ J = 8.4 Hz), 6.87 (d, 1H, ² J _HF = 59 Hz), 6.01 (d, 1H, ³ J _HF = 15.1 Hz). ¹⁹ F NMR: (DMSOd6) δ-114.80, −114.88.

Intermediate 75: 2-Fluoro-5- [1,3] dioxolan-2-yl-benzofuran

5- [1,3] dioxolan-2-yl-benzofuran (50 mg, 0.26 mmol) was dissolved in THF (2 mL) and the solution was cooled to -78 ° C. Butyl lithium (180 mu L, 1.1 eq.) Was added dropwise. The mixture was stirred at 25 ° C. for 30 minutes. The reaction mixture was then cooled to -78 ° C and N-fluorodibenzenesulfonamide (91 mg, 1.1 eq.) Dissolved in 1 mL THF was added dropwise to the reaction mixture. The mixture was stirred overnight at -78 ° C to room temperature. Water and ethyl acetate were added to the mixture and the aqueous layer was extracted three times. The combined organic phases were dried over MgSO ₄ , filtered and evaporated to afford 2-fluoro-5- [1,3] dioxolan-2-yl-benzofuran (75 mg) mixed with byproducts. But it was pure enough for the next step.

The following examples were synthesized:

Example 1: Preparation of 5- (1,3-benzodioxol-5-ylmethylene) -1,3-thiazolidine-2,4-dione

In a 100 ml round bottom flask was placed 20 g thiazolidine, 15.6 g piperonal and 7.7 g beta-alanine in 80 ml acetic acid. The reaction was stirred at 100 ° C. for 3 hours, then slowly cooled to room temperature, washed with acetic acid (room temperature) and water, recrystallized from DME (25 ml) and purified 5- (1,3-benzodioxol-5-ylmethylene ) -1,3-thiazolidine-2,4-dione was obtained. The corresponding potassium salt was obtained via the following route: 5- (1,3-benzodioxol-5-ylmethylene) -1,3-thiazolidine-2,4-dione was suspended in THF, A KOH 1N solution in water (1.0 eq.) Was added. A clear solution was obtained and lyophilized to give pure potassium salt of 5- (1,3-benzodioxol-5-ylmethylene) -1,3-thiazolidine-2,4-dione.

HPLC: 3.48 min. LC-MS: M / Z ESI: 1.31 min, 248.12 (M-1). NMR (parent): ¹ H NMR (DMSO-d 6) δ 12.5 (br. S, 1H), 7.71 (s, 1H), 7.06-7.16 (m, 3H), 6.12 (s, 2H).

If the final compound does not crystallize from the reaction solution, a small amount of water is added to induce a precipitate of the desired condensation product.

The crude is precipitated sufficiently pure from the reaction mixture or recrystallized from a suitable solvent such as DME, methanol, EtOAc or purified by flash chromatography using a mixture of EtOAc, cyclohexane as eluent.

Alternatively, the final compounds can be synthesized in a similar manner according to the following protocol:

An aldehyde corresponding to a similar synthesizer Quest210 ™ was added and a mixture of piperidine (17.9 mg / tube) and 2,4-thiazolidinedione (49.2 mg / tube) in DME (2 ml / tube) was added. The reaction was stirred at 120 ° C. for 3 hours and cooled to room temperature with stirring. ₂ ml of H ₂ O were added. The precipitated compounds were removed by filtration through the lower manifold. The remaining clear solution was reduced in vacuo and then water was added. The solid thus formed was filtered and washed with a small amount of DME to give pure condensation product.

Example 2: Preparation of 5- (1,3-benzodioxol-5-ylmethylene) -2-thioxo-1,3-thiazolidin-4-one

In a 24 ml vial was placed 1 g of commercially available rhodanine, 1.3 g of piperonal and 0.5 ml of TEA in 10 ml of DME. The reaction was stirred at 120 ° C. for 5 hours and then cooled to room temperature to precipitate the final product. The solid was filtered and washed with DME to give 1.6 g (80%) of orange powder.

LC-MS: M / Z ESI: 1.46 min, 266.00 (M + 1), 264.08 (M-1). NMR (parent): ¹ H NMR (DMSO-d6) δ 13. 75 (br. S, 1H), 7.58 (s, 1H), 7.08-7.18 (m, 3H), 6.14 (s, 2H).

Example 3: Preparation of 5- (2,3-dihydro-1,4-benzodioxin-6-ylmethylene) -1,3-thiazolidine-2,4-dione

According to the general method described in Example 1, using 2,3-dihydro-1,4-benzodioxin-6-carbaldehyde and 1,3-thiazolidine-2,4-dione as starting materials, The title compound was obtained.

HPLC: 2.58 min. LC-MS: M / Z ESI: 1.32 min, 262. 16 (M-1). ¹ H NMR: (DMSO-d6) δ 12.52 (br. S, 1H), 7.68 (s, 1H), 7.09 (dd, 2H, J = 1.9, 7.1), 7.00 (d, 1H, J = 9.0 Hz) , 4.36-4.22 (m, 4 H).

Example 4: Preparation of 5- (2,3-dihydro-1-benzofuran-5-ylmethylene) -1,3-thiazolidine-2,4-dione

The title compound was prepared according to the general method described in Example 1, using 2,3-dihydro-1-benzofuran-5-carbaldehyde and 1,3-thiazolidine-2,4-dione as starting materials. Obtained.

HPLC: 3.27 min. LC-MS: M / Z ESI: 1.37 min, 246.18 (M-1). ¹ H NMR: (DMSO-d6) 69.80 (br. S, 1H), 7.37 (s, 1H,), 7.25 (d, 1H, J = 8.3), 7.21 (s, 1H), 6.80 (d, 1H, J = 8.3 Hz), 4.54 (t, 2H, J = 8.85), 3.19 (t, 2H, J = 8.85)

Example 5: Preparation of 5-[(7-methoxy-1,3-benzodioxol-5-yl) methylene] -1,3-thiazolidine-2,4-dione

7-methoxy-1,3-benzodioxol-5-yl) carbaldehyde and 1,3-thiazolidine-2,4-dione as starting materials, according to the general method described in Example 1 The compound of was obtained.

HPLC: 3.57 min. LC-MS: M / Z ESI: 1.30 min, 278.07 (M-1). ¹ H NMR: (DMSOd6) δ 12.63 (br. S, 1H), 7.78 (s, 1H,), 7.65 (s, 1H), 7.57 (d, 1H, J = 8.5 Hz), 7.45 (dd, 2H, J = 0.8, 7.6).

Example 6: Preparation of 5-[(9,10-dioxo-9,10-dihydroanthracen-2-yl) methylene] -1,3-thiazolidine-2,4-dione

(9,10-dioxo-9,10-dihydroanthracen-2-yl) carbaldehyde and 1,3-thiazolidine-2,4-dione as starting materials, to the general method described in Example 1 Thus, the title compound was obtained.

HPLC: 4.12 min. LC-MS: M / Z ESI: 1.50 min, 334.09 (M-1).

Example 7: Preparation of (5-[(2,2-difluoro-1,3-benzodioxol-5-yl) methylene] -1,3-thiazolidine-2,4-dione

General method as described in Example 1, using (2,2-difluoro-1,3-benzodioxol-5-yl) carbaldehyde and 1,3-thiazolidine-2,4-dione as starting materials Thus, the title compound was obtained.

HPLC: 3.85 min. LC-MS (10 min.): M / Z ESI: 3.15 min, 284.11 (M-1). ¹ H NMR: (DMSOd6) δ 12.63 (br. S, 1H), 7.78 (s, 1H), 7.65 (s, 1H), 7.57 (d, 1H, J = 8.5 Hz), 7.45 (dd, 2H, J = 0.8, 7.6)

Example 8: Preparation of 5- (1,3-dihydro-2-benzofuran-5-ylmethylene) -1,3-thiazolidine-2,4-dione

According to the general method described in Example 1, using 1,3-dihydro-2-benzofuran-5-carbaldehyde (intermediate 4) and 1,3-thiazolidine-2,4-dione as starting materials, The title compound was obtained.

HPLC: 2.89 min. LC-MS: M / Z ESI: 1.20 min, 246.20 (M-1). ¹ H NMR: (DMSO-d6) δ 12.60 (br.s, 1H), 7.80 (s, 1H), 7.56-7.42 (m, 2H), 5.03 (s, 4H)

Example 9: Preparation of 5- (1-benzofuran-5-ylmethylene) -1,3-thiazolidine-2,4-dione

Using 1-benzofuran-5-carbaldehyde (intermediate 1) and 1,3-thiazolidine-2,4-dione as starting materials, according to the general method described in Example 1, the title compound was obtained.

HPLC: 3.54 min. LC-MS: M / Z ESI: 1.47 min, 244.20 (M-1). ¹ H NMR: (DMSO-d6) δ 12.58 (br.s, 1H), 8.10 (d, 1H, J = 2.2 Hz), 7.92 (s, 2H), 7.74 (d, 1H, J = 8.6 Hz ), 7.57 (d, 1H, J = 8.6 Hz), 7.07 (s, 1H)

Example 10 5-[(4-methyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-6-yl) methylene] -1,3-thiazolidine-2, Preparation of 4-dione

[(4-Methyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6-yl) carbaldehyde (intermediate 2) and 1,3-thiazolidine-2,4- With dione as the starting material, the title compound was obtained following the general method described in Example 1.

HPLC: 2.79 min. LC-MS: M / Z ESI: 1.19 min, 289.22 (M-1). ¹ H NMR: (DMSO-d6) δ 12.58 (br. S, 1H), 7. 81 (s, 1H), 7.41 (s, 1H), 7.13-7.26 (d, 2H), 4.74 (s, 2H) , 2.99 (s, 3H)

Example 11: Preparation of 5- (1,3-benzodioxol-5-ylmethylene) -2-imino-1,3-thiazolidin-4-one

According to the general method described in Example 1, using 1,3-benzodioxol-5-carbaldehyde and 2-imino-1,3-thiazolidin-4-one as starting materials, the title compound was obtained. It was.

HPLC: 2.29 min. LC-MS: M / Z ESI: 1.21 min, 247.25 (M-1).

Example 12 Preparation of 5-quinolin-6-ylmethylene-thiazolidine-2,4-dione

Using the quinoline-6-carbaldehyde (intermediate 5) and 1,3-thiazolidine-2,4-dione as starting materials, the title compound was obtained according to the general method described in Example 1.

HPLC: 1.445 min. LC-MS: M / Z ESI: 1.17 min, 257.21 (M + l). ¹ H NMR: (DMSO-d6) δ 8.88 (d, J = 6 Hz, 1H), 8.40 (d, J = 9 Hz, 1H), 8.07-7.90 (m, 3H), 7.55 (q, J = 6 Hz, 9 Hz , 1H), 7.45 (s, 1H).

Example 13: 5-quinolin-6-ylmethylene-2-thioxo-thiazolidin-4-one

Using quinoline-6-carbaldehyde (intermediate 5) and rhodanine as starting materials, the title compound was obtained according to the general method described in Example 1.

HPLC: 2.05 min. LC-MS: M / Z ESI: 1.25 min, 273.14 ¹ H NMR: (DMSO-d6) δ 14.00 (br. S, 1H), 8.97 (d, J = 2.3 Hz, 1H), 8.23 (d, J = 9 Hz, 1H), 8.10 (d, J = 9 Hz, 1H), 7.95 (d, J = 9 Hz, 1H), 7.79 (s, 1H), 7.61 (q, J = 3 Hz, 9 Hz, 1H).

Example 14 2-Imino-5-quinolin-6-ylmethylene-thiazolidin-4-one

Using the quinoline-6-carbaldehyde (intermediate 5) and 2-imino-1,3-thiazolidin-4-one as starting materials, the title compound was obtained according to the general method described in Example 1.

HPLC: 1.16 min. LC-MS: M / Z ESI: 1.10 min, 256.18 (M + l). ¹ H NMR: (DMSOd6) δ 12.58 (br. S, 1H), 8.84 (s, 1H), 8.37 (d, J = 6 Hz, 1H), 8.02-7.86 (m, 3H), 7.52 (q, J = 6 Hz, 9 Hz, 1H), 7.26 (s, 1H), 7.02 (b.s, 1H).

Example 15 5- (3-Methyl-benzo [d] isoxazol-5-ylmethylene) -thiazolidine-2,4-dione

According to the general method described in Example 1, using 3-methyl-benzo [d] isoxazole-5-carbaldehyde (intermediate 6) and 1,3-thiazolidine-2,4-dione as starting materials, The title compound was obtained.

HPLC: 2.99 min. LC-MS: M / Z ESI: 1.30 min, 259.17 (M-1). ¹ H NMR: (DMSOd6) δ 12.58 (br. S, 1H), 8.08 (s, 1H), 7.95 (s, 1H), 7.85 (s, 2H), 2.59 (s, 3H).

Example 16: 5- (4-phenyl-quinazolin-6-ylmethylene) -thiazolidine-2,4-dione

Using the 4-phenyl-quinazolin-6-carbaldehyde (intermediate 13) and 1,3-thiazolidine-2,4-dione as starting materials, the title compound was obtained according to the general method described in Example 1. .

HPLC: 3.45 min. LC-MS: M / Z ESI: 1.25 min, 334.15 (M + l). ¹ H NMR: (DMSOd6) δ 12.74 (br.s, 1H), 9.43 (s, 1H), 8.24 (m, 2H), 8.00-7.86 (m, 2H), 7.72-7.66 (m, 5H) .

Example 17 5- (4-Dimethylamino-quinazolin-6-ylmethylene) -thiazolidine-2,4-dione

Using the 4-dimethylamino-quinazolin-6-carbaldehyde (intermediate 14) and 1,3-thiazolidine-2,4-dione as starting materials, the title compound was prepared according to the general method described in Example 1. Obtained.

HPLC: 1.47 min. LC-MS: M / Z ESI: 1.26 min, 301.26 (M + l). ¹ H NMR: (DMSOd6) δ 8.81 (s, 1H), 8.54 (s, 1H), 8.16-7.95 (m, 3H), 7.13-7.26 (d, 2H), 3.63 (s, 6H).

The following examples were synthesized as described in Examples 1 and 17 using Intermediate 15-31 and 1,3-thiazolidine-2,4-dione as starting materials.

Example Intermediate # as starting material Compound name Mass (M + 1) 18 16 5-[(4-aminoquinazolin-6-yl) methylene] -1,3-thiazolidine-2,4-dione 273.29 19 15 5-[(4-piperidin-1-ylquinazolin-6-yl) methylene] -1,3-thiazolidine-2,4-dione 341.40 20 22 5-[(4-morpholin-4-ylquinazolin-6-yl) methylene] -1,3-thiazolidine-2,4-dione 343.20 21 17 5-{[4- (benzylamino) quinazolin-6-yl] methylene} -1,3-thiazolidine-2,4-dione 363.10 22 21 5-{[4-diethylamino) quinazolin-6-yl] methylene} -1,3-thiazolidine-2,4-dione 329.30 23 18 5-({4-[(pyridin-2-ylmethyl) amino] quinazolin-6-yl} methylene) -1,3-thiazolidine-2,4-dione 364.40 24 19 5-({4-[(pyridin-3-ylmethyl) amino] quinazolin-6-yl} methylene) -1,3-thiazolidine-2,4-dione 364.40 25 23 Ethyl 1- {6-[(2,4-dioxo-1,3-thiazolidine-5-ylidene) methyl] quinazolin-4-yl} piperidine-3-carboxylate 413.20 26 25 Ethyl 1- {6-[(2,4-dioxo-1,3-thiazolidine-5-ylidene) methyl] quinazolin-4-yl} piperidine-4-carboxylate 413.30 27 24 tert-butyl 1- {6-[(2,4-dioxo-1,3-thiazolidin-5-ylidene) methyl] quinazolin-4-yl} -L-prolinate 427.20 28 20 5-{[4- (4-methylpiperazin-1-yl) quinazolin-6-yl] methylene} -1,3-thiazolidine-2,4-dione 356.13 29 31 5-{[4- (4-pyrimidin-2-ylpiperazin-1-yl) quinazolin-6-yl] methylene} -1,3-thiazolidine-2,4-dione 420.20 30 30 5-({4- [4- (4-fluorophenyl) piperidin-1-yl] quinazolin-6-yl} methylene) -1,3-thiazolidine-2,4-dione 435.30 31 29 5-{[4- (4-benzylpiperidin-1-yl) quinazolin-6-yl] methylene} -1,3-thiazolidine-2,4-dione 431.30 32 28 5-({4- [4- (2-phenylethyl) piperidin-1-yl] quinazolin-6-yl} methylene) -1,3-thiazolidine-2,4-dione 445.40 33 27 5-{[4- (4-methylpiperidin-1-yl) quinazolin-6-yl] methylene} -1,3-thiazolidine-2,4-dione 355.20 34 26 5-{[4- (4-hydroxypiperidin-1-yl) quinazolin-6-yl] methylene} -1,3-thiazolidine-2,4-dione 357.40

Example 35 1- [6- (2,4-Dioxo-thiazolidine-5-ylidenemethyl) -quinazolin-4-yl] -piperidine-4-carboxylic acid

Ethyl 1- {6-[(2,4-dioxo-1,3-thiazolidine-5-ylidene) methyl] quinazolin-4-yl} piperidine-4-carboxylate (Example 26) 50 mg was dissolved in a 2 ml solution of THF / water (1/1). A few drops of 5N NaOH were added and the reaction stirred for 12 hours at room temperature. After the reaction was completed, the solvent was evaporated and the title compound precipitated as a yellow solid in diethyl ether (40 mg, 82%).

HPLC: 1.43 min. LC-MS: M / Z ESI: 1.15 min, 385.20 (M + l).

Example 36 1- [6- (2,4-Dioxo-thiazolidine-5-ylidenemethyl) -quinazolin-4-yl] -piperidine-3-carboxylic acid

According to the general method described in Example 35, the title compound was obtained.

HPLC: 1.50 min. LC-MS: M / Z ESI: 1.10 min, 385.40 (M + l).

Example 37 1- [6- (2,4-dioxo-thiazolidine-5-ylidenemethyl) -quinazolin-4-yl] pyrrolidine-2-carboxylic acid

tert-butyl 1- {6-[(2,4-dioxo-1,3-thiazolidin-5-ylidene) methyl] quinazolin-4-yl} -L-prolinate (Example 27) 10 mg was stirred in 25% (TFA / DCM) solution for 12 hours at room temperature. The solvent was evaporated in vacuo and the expected compound was precipitated with diethyl ether to give pure 1- [6- (2,4-dioxo-thiazolidin-5-ylidenemethyl) -quinazolin-4-yl] pi. Obtained ralidin-2-carboxylic acid (7 mg, 81%).

HPLC: 1.43 min. LC-MS: M / Z ESI: 1.10 min, 371.30 (M + l).

Example 38: 5- (4-Methylamino-quinazolin-6-ylmethylene) -thiazolidine-2,4-dione

Following the general method described in Example 1, using 4-methylamino-quinazolin-6-carbaldehyde (intermediate 11) and 1,3-thiazolidine-2,4-dione as starting materials, the title compound was Obtained.

HPLC: 1.43 min. LC-MS: M / Z ESI: 1.03 min, 287.19 (M + l). ¹ H NMR: (DMSO-d6) δ 11.97 (br. S, 1 H), 8.53 (br. S, 2 H), 8.37 (s, 1 H), 7.92 (d, J = 8 Hz, 1 H), 7.76 (s, 2H), 3.03 (s, 3H)

Example 39: 5- (4-methoxy-quinazolin-6-ylmethylene) -thiazolidine-2,4-dione

Using the 4-methoxy-quinazolin-6-carbaldehyde (intermediate 10) and 1,3-thiazolidine-2,4-dione as starting materials, the title compound was obtained according to the general method described in Example 1. It was.                 

HPLC: 2.57 min. LC-MS: M / Z ESI: 1.12 min, 288. 20 (M + l). ¹ H NMR: (DMSOd6) δ 12.74 (br.s, 1H), 8.86 (s, 1H), 8.32 (s, 1H), 8.11 (m, 1H), 8.03-7.98 (m, 2H), 4.18 (s, 3H)

Example 40 2-Imino-5- (4-methylamino-quinazolin-6-ylmethylene) -thiazolidin-4-one

4-Methylamino-quinazolin-6-carbaldehyde (Intermediate 11) and 2-imino-1,3-thiazolidin-4-one as starting materials, according to the general method described in Example 1 The compound was obtained.

HPLC: 2.43 min. LC-MS: M / Z ESI: 1.07 min, 286.14 (M + l).

Example 41 2-Imino-5- (4-piperidine-quinazolin-6-ylmethylene) -thiazolidin-4-one

4-Piperidine-quinazolin-6-carbaldehyde (intermediate 72) and 2-imino-1,3-thiazolidin-4-one as starting materials, according to the general method described in Example 1 The compound of was obtained.

HPLC: 1.78 min. LC-MS: M / Z ESI: 1.40 min, 340.26 (M + l). ¹ H NMR: (DMSO-d6) δ 8.76 (s, 1H), 8.18 (s, 1H), 8.16 (d, J = 6 Hz, 1H), 7.88 (d, J = 9 Hz, 1H), 7.80 (s , 1H), 4.09 (s, 4H), 1.80 (s, 6H).

Example 42: 2-Imino-5- (4-dimethylamino-quinazolin-6-ylmethylene) -thiazolidin-4-one

4-Piperidine-quinazolin-6-carbaldehyde (intermediate 14) and 2-imino-1,3-thiazolidin-4-one as starting materials, according to the general method described in Example 1 The compound of was obtained.

HPLC: 1.32 min. LC-MS (10 min.): M / Z ESI: 1.54 min, 300.23 (M + l). ¹ H NMR: (DMSO-d6) δ8.82 (s, 1H), 8.53 (s, 1H), 8.16 (d, J = 9 Hz, 1H), 7.87 (t, J = 9 Hz, 2H), 3.65 (s , 6H).

Example 43: 5- (2-Methyl-2H-benzotriazol-5-ylmethylene) -thiazolidine-2,4-dione

Using 2-methyl-2H-benzotriazole-5-carbaldehyde (intermediate 33) and thiazolidinedione as starting materials, the title compound was obtained following the general method described in Example 1.

HPLC: 2.68 min. ¹ H NMR: (DMSO-d6) δ 12.58 (br. S, 1 H), 7.98 (s, 1 H), 7.92 (d, J = 9 Hz, 1 H), 7.62 (d, J = 6 Hz, 1 H), 7.43 (s, 1 H), 4.48 (s, 3 H).

Example 44 5- (3-Methyl-3H-benzotriazol-5-ylmethylene) -thiazolidine-2,4-dione

Using the 3-methyl-3H-benzotriazole-5-carbaldehyde (intermediate 34) and thiazolidinedione as starting materials, the title compound was obtained following the general method described in Example 1.

HPLC: 2.35 min. LC-MS: M / Z ESI: 1.22 min, 259.23 (M-1). ¹ H NMR: (DMSO-d6) δ 12.58 (br.s, 1H), 8.17 (d, J = 9 Hz, 1H), 8.07 (s, 1H), 7.62 (d, J = 6 Hz, 1H), 7.47 ( s, 1 H), 4.33 (s, 3 H).

Example 45 5- (3-ethyl-3H-benzimidazol-5-ylmethylene) -thiazolidine-2,4-dione

5- (4-Amino-3-ethylamino-benzylidene) -thiazoline-2,4-dione (50 mg, 0.19 mmol) (Intermediate 36) is dissolved in formic acid (5 mL) and the solution overnight at 100 ° C. Stirred. Formic acid was then removed under vacuum. The crude residue was purified by silica gel column to give the title compound.

HPLC: 1.71 min. LC-MS: M / Z ESI: 0.82 min, 274.21 (M + l).

The following examples were synthesized as described in Example 45 using intermediates 37-54 and 1,3-thiazolidine-2,4-dione as starting materials.

Example Intermediate as starting material Compound name Mass (M + 1) 46 37 5-{[1- (4-phenylbutyl) -1H-benzimidazol-6-yl] methylene} -1,3-thiazolidine-2,4-dione 378.30 47 50 5-[(1-prop-2-yn-1-yl-1H-benzimidazol-yl) methylene] -1,3-thiazolidine-2,4-dione 284.24 48 38 5-[(1- {2- [4- (trifluoromethyl) phenyl] ethyl} -1H-benzimidazol-6-yl) methylene] -1,3-thiazolidine-2,4-dione 418.17 49 39 5-({1- [2- (4-hydroxyphenyl) ethyl] -1H-benzimidazol-6-yl} methylene) -1,3-thiazolidine-2,4-dione 366.26 50 40 Methyl 4- {6-[(2,4-dioxo-1,3-thiazolidine-5-ylidene) methyl] -1H-benzimidazol-1-yl} cyclohexanecarboxylate 386.35 51 41 5-({1- [2- (5-methoxy-1H-indol-3-yl) ethyl] -1H-benzimidazol-6-yl} methylene) -1,3-thiazolidine-2,4 Dion 419.21 52 42 5-({1-[(1-methyl-1H-pyrazol-4-yl) methyl] -1H-benzimidazol-6-yl} methylene) -1,3-thiazolidine-2,4-dione 340.99 53 43 5-({1- [2- (3,4-dimethoxyphenyl) ethyl] -1H-benzimidazol-6-yl} methylene) -1,3-thiazolidine-2,4-dione 410.37 54 54 5-({1- [2- (4-phenoxyphenyl) ethyl] -1H-benzimidazol-6-yl} methylene) -1,3-thiazolidine-2,4-dione 442.51 55 44 5-({1- [4- (trifluoromethyl) benzyl-1H-benzimidazol-6-yl} methylene) -1,3-thiazolidine-2,4-dione 404.16 56 45 4- {6-[(2,4-dioxo-1,3-thiazolidine-5-ylidene) methyl] -1H-benzimidazol-1-yl} cyclohexanecarboxylic acid 372.18 57 46 5-[(1-isobutyl-1H-benzimidazol-6-yl) methylene] -1,3-thiazolidine-2,4-dione 302.25 58 47 5-({1- [2- (1,3-benzodioxol-4-yl) ethyl] -1H-benzimidazol-6-yl} methylene) -1,3-thiazolidine-2,4- Dion 394.27 59 48 5-({1- [2- (2-phenoxyphenyl) ethyl] -1H-benzimidazol-6-yl} methylene) -1,3-thiazolidine-2,4-dione 442.29 60 49 5-{[1- (3,3-diphenylpropyl) -1H-benzimidazol-6-yl] methylene} -1,3-thiazolidine-2,4-dione 440.27 61 51 5-{[1- (2-methoxybenzyl) -1H-benzimidazol-6-yl] methylene} -1,3-thiazolidine-2,4-dione 366.33 62 52 5-{[1- (3-furylmethyl) -1H-benzimidazol-6-yl] methylene} -1,3-thiazolidine-2,4-dione 326.24 63 53 5-[(1-propyl-1H-benzimidazol-6-yl) methylene] -1,3-thiazolidine-2,4-dione 288.18

Example 64 5-quinoxaline-6-ylmethylene-thiazolidine-2,4-dione

Using the quinoxaline-6-carbaldehyde (intermediate 55) and thiazolidinedione as starting materials, according to the general method described in Example 1, the title compound was obtained.

HPLC: 2.48 min. LC-MS: M / Z ESI: 1.01 min, 256.20 (M-1). ¹ H NMR: (DMSOd6) δ 12.58 (br.s, 1H), 8.93 (d, J = 9 Hz, 2H), 8.18 (s, 1H), 8.10 (d, J = 9 Hz, 1H), 8.03 ( d, J = 9 Hz, 1 H), 7.51 (s, 1 H).

Example 65 5-quinoxalin-6-ylmethylene-2-thioxo-thiazolidin-4-one

Using the quinoxaline-6-carbaldehyde (intermediate 55) and rhodanine as starting materials, according to the general method described in Example 1, the title compound was obtained.

HPLC: 3.10 min. LC-MS: M / Z ESI: 1.17 min, 272.13 (M-1). ¹ H NMR: (DMSOd6) δ 12.00 (br. S, 1H), 9.02 (s, 2H), 8.31 (s, 1H), 8.21 (d, J = 9 Hz, 1H), 8.04 (d, J = 9 Hz, 1 H), 7.90 (s, 1 H)

Example 66 2-Imino-5-quinoxalin-6-ylmethylene-thiazolidin-4-one

Using the quinoxaline-6-carbaldehyde (intermediate 55) and 2-imino-1,3-thiazolidin-4-one as starting materials, according to the general method described in Example 1, the title compound was obtained. .

HPLC: 1.97 min. LC-MS: M / Z ESI: 1.02 min, 255.19 (M-1). ¹ HNMR: (DMSOd6) δ 9.57-9.30 (b.d, J = 81 Hz, 2H), 9.00 (s, 2H), 8.26-8.07 (m, 3H), 7.84 (s, 1H).

Example 67 5-benzothiazol-6-ylmethylene-thiazolidine-2,4-dione

Using the quinoxaline-6-carbaldehyde (intermediate 56) and thiazolidinedione as starting materials, according to the general method described in Example 1, the title compound was obtained.

HPLC: 2.85 min. LC-MS: M / Z ESI: 1.06 min, 261.11 (M-1) ¹ H NMR: (DMSO-d6) δ 12.58 (br. S, 1H), 9.39 (s, 1H), 8.27 (s, 1H) , 8.11 (d, J = 9 Hz, 1H), 7.70 (d, J = 9 Hz, 1H), 7.42 (s, 1H).

Example 68: 5- (3-Methyl-benzofuran-5-ylmethylene) -thiazolidine-2,4-dione

Following the general method described in Example 1, using 3-methyl-benzofuran-5-carbaldehyde (intermediate 57) and 1,3-thiazolidine-2,4-dione as starting materials, the title compound was obtained. It was.

HPLC: 1.47 min. LC-MS: M / Z ESI: 1.15 min, 257.21 (M-1). ¹ H NMR: (DMSOd6) δ 12.50 (br.s, 1H), 8.87 (d, J = 6 Hz, 1H), 8.38 (d, J = 9HZ, 1H), 8.07 (t, J = 12 Hz, 2H ), 7.92 (d, J = 9 Hz, 1 H), 7.53 (q, J = 6 Hz, 12 Hz, 1 H), 7.45 (s, 1 H).

Example 69 5- (2-Bromo-3-methyl-benzofuran-5-ylmethylene) -thiazolidine-2,4-dione

In a 25 ml 3-neck flask, 5- (3-methyl-benzofuran-5-ylmethylene) -thiazolidine-2,4-dione (100 mg, 0.39 mmol) (Example 68) and Br in 2 ml of AcOH at 0 ° C. ₂ (20 μl, 1 eq.) Was added. The mixture was allowed to warm to room temperature. After 2 hours at room temperature, another equivalent of Br ₂ was added. After 3 hours the reaction was filtered to give the title compound, yellow product (87 mg, 66%).

LC-MS: M / Z ESI: 1.69 min, 339.8 (M + l). ¹ H NMR: (DMSOd6) δ 12.50 (br. S, 1H), 7.93 (s, 1H), 7.82 (s, 1H), 7.72 (d, J = 6 Hz, 1H), 7.54 (d, J = 6 Hz, 1 H), 2.20 (s, 3 H).

Example 70 5- (3-Bromo-benzofuran-5-ylmethylene) -thiazolidine-2,4-dione

According to the general method described in Example 1, starting with 3-bromo-benzofuran-5-carbaldehyde (Intermediate 58) and 1,3-thiazolidine-2,4-dione, the title compound was Obtained.

HPLC: 3.92 min. LC-MS: M / Z ESI: 1.57 min, 325.17 (M + l). ¹ H NMR: (DMSO-d6) δ 12.60 (br. S, 1H), 8.42 (s, 1H), 8.00 (s, 1H), 7.85 (d, J = 23 Hz, 1H), 7.76 (s, 1H) , 7.63 (d, J = 23 Hz, 1 H).

Example 71 3- [5- (2,4-dioxo-thiazolidine-5-ylidenemethyl) -benzofuran-3-yl] -acrylic acid ethyl ester

To the general method described in Example 1 using 3- (5-formyl-benzofuran-3-yl) -acrylic acid ethyl ester (intermediate 60) and 1,3-thiazolidine-2,4-dione as starting materials Thus, the title compound was obtained.

HPLC: 4.00 min. LC-MS: M / Z ESI: 1.60 min, 342.20 (M-1). ¹ H NMR: (DMSOd6) δ 12.50 (br.s, 1H), 8.63 (s, 1H), 8.42 (s, 1H), 8.08 (s, 1H), 7.83 (m, 2H), 7.62 (s, 1H), 4.22 (q, J = 6 Hz, 9 Hz, 2H), 1.28 (t, J = 9 Hz, 3H).

Example 72: 3- [5- (2,4-Dioxo-thiazolidine-5-ylidenemethyl) -benzofuran-3-yl] -acrylic acid

3- [5- (2,4-dioxo-thiazolidine-5-ylidenemethyl) -benzofuran-3-yl] -acrylic acid ethyl ester (205 mg, 0.6 mmol) (Example 71) was prepared by THF / water. Dissolved in 4: 2. 81 mg ( ₄ eq.) Of LiOH.H ₂ O were added to this solution while stirring. The reaction was stirred for 15 hours. The solvent was evaporated and the residue precipitated with ether. The solid was washed with 1N HCl and dried to give 170 mg (90%) of pure 3- [5- (2,4-dioxo-thiazolidine-5-ylidenemethyl) -benzofuran-3-yl] -acrylic acid. It was.

HPLC: 3.25 min. LC-MS: M / Z ESI: 1.01 min, 314.11 (M-1). ¹ H NMR: (DMSO-d6) δ 8.22 (s, 1H), 8.03 (s, 1H), 7.58 (dd, J = 9 Hz, 33 Hz, 2H), 7.43 (s, 1H), 7.25 (d, J = 18 Hz, 1H), 7.07 (s, 1H).

Example 73: 5- [3- (3-oxo-3-piperidin-1-yl-propenyl) -benzofuran-5-ylmethylene] -thiazolidine-2,4-dione

180 mg (0.57 mmol) of 3- [5- (2,4-dioxo-thiazolidine-5-ylidenemethyl) -benzofuran-3-yl] -acrylic acid (Example 72) was suspended in THF (25 ml). I was. To this suspension was added DIEA (2eq.) And piperidine (3eq.). PyBOP (1.5 eq.) Was added with stirring. After 30 minutes, the reaction mixture became clear and after 1 hour a precipitate formed. The reaction was stirred overnight. The precipitate was filtered off and washed with THF and 1N HCl to afford the title compound in high purity.

HPLC: 3.91 min. LC-MS: M / Z ESI: 1.58 min, 383.22 (M + l). ¹ H NMR: (DMSO-d6) δ 8.46 (s, 1H), 8.19 (s, 1H), 7.71-7.51 (m, 4H), 7.23 (d, J = 15 Hz, 1H), 3.73 (d, J = 48 Hz, 2H), 1.51 (d, J = 36Hz, 3H).

The following amides were synthesized according to the synthesis method of Example 73.

Example Amine as starting material Compound name Mass (M + 1) 74 Proline-Methyl Ester Methyl 1-((3- {5-[(2,4-dioxo-1,3-thiazolidin-5-ylidene) methyl] -1-benzofuran-3-yl} prop-2-eno Prolinate 427.15 75 D-proline-methyl ester Methyl 1-((3- {5-[(2,4-dioxo-1,3-thiazolidin-5-ylidene) methyl] -1-benzofuran-3-yl} prop-2-eno Yl) -D-prolinate 413.15 76 Pyrrolidine (5-({3-[(3-oxo-3-pyrrolidin-1-ylprop-1-en-1-yl] -1-benzofuran-5-yl} methylene) -1,3- Thiazolidine-2,4-dione 369.52 77 Morpholine 5-({3- [3-morpholin-4-yl-3-oxoprop-1-en-1-yl] -1-benzofuran-5-yl} methylene) -1,3-thiazolidine -2,4-dione 385.07 78 L-Proline-Methyl Ester Methyl 1- (3- {5-[(2,4-dioxo-1,3-thiazolidin-5-ylidene) methyl] -1-benzofuran-3-yl} prop-2-enoyl ) -L-prolinate 427.13 79 N-methyl-cyclohexylamine N-cyclohexyl-3- {5-[(2,4-dioxo-1,3-thiazolidin-5-ylidene) methyl] -1-benzofuran-3-yl} -N-methylacrylamide 411.12 80 N-ethyl-hydroxyethylamine 3- {5-[(2,4-dioxo-1,3-thiazolidine-5-ylidene) methyl] -1-benzofuran-3-yl} -N-ethyl-N- (2-hydr Oxyethyl) acrylamide 387.10 81 Cyclobutylamine N-cyclobutyl-3- {5-[(2,4-dioxo-1,3-thiazolidin-5-ylidene) methyl] -1-benzofuran-3-yl} acrylamide 369.13 82 Azetidine 5-({3- [3-azetidin-1-yl-3-oxoprop-1-en-1-yl] -1-benzofuran-5-yl} methylene) -1,3-thiazolidine -2,4-dione 355.64 83 1,3-dihydro-2H-isoindole 5-({3- [3- (1,3-Dihydro-2H-isoindol-2-yl) -3-oxoprop-1-en-1-yl] -1-benzofuran-5-yl Methylene) -1,3-thiazolidine-2,4-dione 415.00
(M-1) 84 Ajay Pan 5-({3- [3-Azepan-1-yl-3-oxoprop-1-en-1-yl] -1-benzofuran-5-yl} methylene) -1,3-thiazolidine -2,4-dione 397.46 85 Piperidin-1-ylamine 3- {5-[(2,4-dioxo-1,3-thiazolidine-5-ylidene) methyl] -1-benzofuran-3-yl} -N-piperidin-1-ylacrylic amides 398.00 86 Pyridin-3-yl-methylamine 3- {5-[(2,4-dioxo-1,3-thiazolidine-5-ylidene) methyl] -1-benzofuran-3-yl} -N- (pyridin-3-ylmethyl) Acrylamide 406.10 87 Cyclohexylamine N-cyclohexyl-3- {5-[(2,4-dioxo-1,3-thiazolidin-5-ylidene) methyl] -1-benzofuran-3-yl} -acrylamide 397.08 88 4-N-methyl-piperazine 5-({3- [3- (4-methylpiperazin-1-yl) -3-oxoprop-1-en-1-yl] -1-benzofuran-5-yl} methylene) -1, 3-thiazolidine-2,4-dione 398.02 89 Cycloheptylamine N-cycloheptyl-3- {5-[(2,4-dioxo-1,3-thiazolidin-5-ylidene) methyl] -1-benzofuran-3-yl] acrylamide 411.44 90 Pyrroline 5-({3- [3- (2,5-Dihydro-1H-pyrrol-1-yl) -3-oxoprop-1-en-1-yl] -1-benzofuran-5-yl} Methylene) -1,3-thiazolidine-2,4-dione 367.11 91 Cyclopentylamine N-cyclopentyl-3- {5-[(2,4-dioxo-1,3-thiazolidin-5-ylidene) methyl] -1-benzofuran-3-yl} acrylamide 383.11

Example 92 3- [5- (2,4-dioxo-thiazolidine-5-ylidenemethyl) -benzofuran-3-yl] -propionic acid ethyl ester

In the general method described in Example 1, using 3- (5-formyl-benzofuran-3-yl) -propionic acid ethyl ester (intermediate 71) and 1,3-thiazolidine-2,4-dione as starting materials Thus, the title compound was obtained.

HPLC: 3.94 min. LC-MS: M / Z ESI: 2.87 min, 346.15 (M + l). ¹ H NMR: (DMSO-d6) (δ 12.58 (br. S, 1H), 7.92 (d, J = 6 Hz, 3H), 7.72 (d, J = 9 Hz, 1H), 7.53 (d, J = 9 Hz, 1H), 4.03 (q, J = 9 Hz, 15 Hz, 2H), 2.94 (t, J = 9 Hz, 2H), 2.73 (t, J = 6 Hz, 2H), 1.14 (t, J = 6 Hz).

Example 93: 3- [5- (2,4-Dioxo-thiazolidine-5-ylidenemethyl) -benzofuran-3-yl] -propionic acid

The standard saponification technique described in Example 72 was applied using Example 92 as the starting material to afford the title compound.

HPLC: 3.09 min. LC-MS (10 min.): M / Z ESI: 1.19 min, 316.14 (M-1). ¹ H NMR: (DMSOd6) δ 12.58 (br.s, 1H), 12.22 (b.s, 1H), 7.93 (d, J = 12 Hz, 3H), 7.70 (d, J = 9 Hz, 1H), 7.54 (d, J = 9 Hz, 1H), 2.91 (t, J = 9 Hz, 2H), 2.65 (t, 6 Hz, 2H).

Example 94: 5- [3- (3-oxo-3-piperidin-1-yl-propyl) -benzofuran-5-ylmethylene] -thiazolidine-2,4-dione

Example 93 was used as starting material to apply the synthesis protocol described in Example 73 to afford the title compound.

HPLC: 3.783 min. LC-MS: M / Z ESI: 1.46 min, 385. 14 (M + l). ¹ H NMR: (DMSOd6) δ 12.66 (br. S, 1H), 8.06 (s, 3H), 8.01 (s, 1H), 7.79 (s, 1H), 3.50-1.60 (m, 14H).

Example 95 6- (2,4-dioxo-thiazolidine-5-ylidenemethyl) -2,3-dihydro-benzo [1,4] oxazine-4-carboxylic acid tert-butyl ester

6-formyl-2,3-dihydro-benzo [1,4] -oxazine-4-carboxylic acid tert-butyl ester (intermediate 62) and 1,3-thiazolidine-2,4-dione as starting materials Thus, according to the general method described in Example 1, the title compound was obtained.

HPLC: 2.52 min. LC-MS: M / Z ESI: min, 261.21 (M-Boc-1).

Example 96: 5- (3,4-Dihydro-2H-benzo [1,4] oxazin-6-ylmethylene) -thiazolidine-2,4-dione

100 mg of 6-formyl-2,3-dihydro-benzo [1,4] oxazine-4-carboxylic acid tert-butyl ester (intermediate 62) was treated with TFA / DCM 25% for 2 hours. The solvent was evaporated to dryness and the residue was used for the Knoevenagel reaction described in Example 1 without further purification to afford the title compound as a yellow solid.

HPLC: 2.56 min. LC-MS: M / Z ESI: 1.14 min, 261.24 (M-1). ¹ H NMR: (DMSOd6) δ 12.58 (br.s, 1H), 7.57 (s, 1H), 6.78 (s, 3H), 4.17 (t, J = 3 Hz, 2H), 3.28 (t, J = 6 Hz, 2H).

Example 97: 5- (4-benzoyl-3,4-dihydro-2H-benzo [1,4] oxazin-6-ylmethylene) -thiazolidine-2,4-dione

5- (3,4-Dihydro-2H-benzo [1,4] oxazin-6-ylmethylene) -thiazolidine-2,4-dione (Example 96) in 4 ml anhydrous THF (35 mg, 0.13 mmol) ) Was treated with benzoyl chloride (156 μl, 10eq.) In the presence of DIEA (2eq.) For 3 hours. Excess benzoyl chloride was hydrolyzed, EtOAc was added and the organic phase was washed with NaHCO ₃ and brine. The crude was purified on silica gel using EtOAc / cyclohexane 3: 7 as eluent to afford 14 mg (35%) of the title compound.

HPLC: 4.57 min. LC-MS: M / Z ESI: 2.11 min, 364.91 (M-1).

The following example was synthesized by the same method described in Example 97.

Example 98 5- (4-acetyl-3,4-dihydro-2H-benzo [1,4] oxazin-6-ylmethylene) -thiazolidine-2,4-dione

Yield = 43 mg (95%).

HPLC: 2.65 min. LC-MS: M / Z ESI: 1.12 min, 305. 24 (M + l). ¹ H NMR: (DMSOd6) δ 12.58 (br.s, 1H), 8.30 (bs, 1H), 7.71 (s, 1H), 7.35 (d, J = 9 Hz, 1H), 7.05 (d, J = 9 Hz, 1 H), 4.33 (t, J = 6 Hz, 2H), 4.00 (t, J = 6 Hz, 2H).

Example 99 6- (2,4-dioxo-thiazolidine-5-ylidenemethyl) -benzo [1,4] oxazine-4-carboxylic acid tert-butyl ester

General described in Example 1 using 6-formyl-benzo [1,4] oxazine-4-carboxylic acid tert-butyl ester (intermediate 63) and 1,3-thiazolidine-2,4-dione as starting materials According to the method, the title compound was obtained.

HPLC: 4.23 min. LC-MS: M / Z ESI: 1.82 min, 359.16 (M-1). ¹ H NMR: (DMSO-d6) δ 12.50 (br.s, 1H), 7.63 (d, J = 3 Hz, 2H), 7.31 (d, J = 3 Hz, 1H), 6.95 (d, J = 6 Hz, 1H ), 6.30 (s, 2 H).

Example 100: [6- (2,4-Dioxo-thiazolidine-5-ylidenemethyl) -3-oxo-2,3-dihydro-benzo [1,4] -oxazine-4- Yl] -acetic acid methyl ester

(6-formyl-3-oxo-2,3-dihydro-benzo [1,4] oxazin-4-yl) -acetic acid methyl ester (intermediate 64) and 1,3-thiazolidine-2,4- With dione as the starting material, the title compound was obtained following the general method described in Example 1.

HPLC: 2.83 min. LC-MS: M / Z ESI: 1.20 min, 347.25 (M-1). ¹ H NMR: (DMSOd6) δ 12.58 (br.s, 1H), 7.76 (s, 1H), 7.36 (s, 1H), 7.20 (m, 2H), 4.82 (d, J = 15 Hz, 4H) , 3.71 (s, 3 H).

Example 101 N-benzyl-2- [6- (2,4-dioxo-thiazolidine-5-ylidenemethyl) -3-oxo-2,3-dihydro-benzo [1,4] ox Photo-4-yl] -acetamide

[6- (2,4-Dioxo-thiazolidine-5-ylidenemethyl) -3-oxo-2,3-dihydro-benzo [1,4] -oxazin-4-yl] -methyl acetate Ester (195 mg, 0.56 mmol) (Example 100) was saponified using LiOH 2eq. As described in Example 74 to [6- (2,4-dioxo-thiazolidine-5-ylidenemethyl)- 3-oxo-2,3-dihydro-benzo [1,4] oxazin-4-yl] -acetic acid was obtained. The acid (50 mg, 0.15 mmol) thus obtained was dissolved in THF. HOBt (32 mg, 1.5 eq.), EDC (43 mg, 1.5 eq.) And benzylamine (25 mg, 1.5 eq.) Were added with stirring. The reaction mixture was stirred at rt for 15 h. EtOAc was added and the organic phase was washed three times with 1N HCl, NaHCO ₃ , brine each. After evaporation of the solvent the crude residue was purified on silica gel using DCM / EtOAc as eluent to afford the title compound as a colorless powder (35 mg, 54%).

HPLC: 3.06 min. LC-MS: M / Z ESI: 1.27 min, 424.21 (M + l).

Example 102 5- (4-butyl-3-oxo-3,4-dihydro-2H-benzo [1,4] oxazin-6-ylmethylene) -thiazolidine-2,4-dione

Starts 4-butyl-3-oxo-3,4-dihydro-2H-benzo [1,4] oxazine-6-carbaldehyde (intermediate 65) and 1,3-thiazolidine-2,4-dione As a material, the title compound was obtained according to the general method described in Example 1.

HPLC: 3.67 min. LC-MS: M / Z ESI: 1.49 min, 331.23 (M-1). ¹ H NMR: (DMSOd6) δ 12.58 (br. S, 1H), 7.85 (s, 1H), 7.43 (s, 1H), 7.24 (d, J = 6 Hz, 1H), 7.15 (d, J = 9 Hz, 1H), 4.73 (s, 2H), 3.91 (t, J = 3 Hz, 2H), 1.57 (m, 2H), 1.36 (m, 2H), 0.91 (t, J = 9 Hz, 3H).

Example 103: 5- (4-benzyl-3-oxo-3,4-dihydro-2H-benzo [1,4] oxazin-6-ylmethylene) -thiazolidine-2,4-dione

Starts 4-benzyl-3-oxo-3,4-dihydro-2H-benzo [1,4] oxazine-6-carbaldehyde (intermediate 66) and 1,3-thiazolidine-2,4-dione As a material, the title compound was obtained according to the general method described in Example 1.

HPLC: 3.67 min. LC-MS: M / Z ESI: 1.46 min, 365.17 (M-1). ¹ H NMR: (DMSOd6) δ 12.58 (br. S, 1H), 7.68 (s, 1H), 7.38-7.22 (m, 8H), 5.24 (s, 2H), 4.97 (s, 2H).

Example 104 5- (2-Chloro-benzofuran-5-ylmethylene-thiazolidine-2,4-dione

General described in Example 1 using 2-chloro-5- [1,3] dioxolan-2-yl-benzofuran (intermediate 67) and 1,3-thiazolidine-2,4-dione as starting materials According to the method, the title compound was obtained.

HPLC: 3.84 min. LC-MS: M / Z ESI: 1.62 min, 278.12 (M-1). ¹ H NMR: (DMSOd6) δ 7.90-7.75 (m, 2H), 7.68 (d, J = 9 Hz, 1H), 7.52 (d, J = 9 Hz, 1H), 7.09 (s, 1H).

Example 105: 5- (3-amino-benzo [d] isoxazol-5-ylmethylene) -thiazolidine-2,4-dione

Titled according to the general method described in Example 1, using 3-amino-benzo [d] isoxazole-5-carbaldehyde (intermediate 68) and 1,3-thiazolidine-2,4-dione as starting materials The compound of was obtained.

HPLC: 2.45 min. LC-MS: M / Z ESI: 0.97 min, 260.17 (M-1). ¹ H NMR: (DMSO-d6) δ 12.60 (br. S, 1H), 8.01 (s, 1H), 7.85 (s, 1H), 7.60 (d, J = 9 Hz, 1H), 6.67 (s, 1H) .

Example 106 5- (3-phenylethynyl-benzofuran-5-ylmethylene) -thiazolidine-2,4-dione

The title compound, according to the general method described in Example 1, using 3-phenylethynyl-benzofuran-5-carbaldehyde (intermediate 59) and 1,3-thiazolidine-2,4-dione as starting materials. Obtained.

HPLC: 4.82 min. LC-MS: M / Z ESI: 2.02 min, 344.18 (M-1). ¹ H NMR: (DMSO-d6) δ 12.58 (br. S, 1H), 8.49 (s, 1H), 7.92 (s, 1H), 7.72 (d, J = 9 Hz, 1H), 7.62 (m, 3H) , 7.45 (m, 4 H).

Example 107 5-benzo [1,2,5] thiadiazol-5-ylmethylene-thiazolidine-2,4-dione

According to the general method described in Example 1, using 2,1,3-benzothiadiazole-5-carbaldehyde and 1,3-thiazolidine-2,4-dione as starting materials, the title compound was obtained. It was.

HPLC: 3.03 min. LC-MS: M / Z ESI: 1.14 min, 262.11 (M-1). ¹ H NMR: (DMSOd6) δ 12.58 (br. S, 1H), 8.11 (m, 2H), 7.90 (d, J = 9 Hz, 1H), 7.47 (s, 1H).

Example 108 5-benzo [1,2,5] oxadiazol-5ylmethylene-thiazolidine-2,4-dione

According to the general method described in Example 1, using the 2,1,3-benzoxadiazole-5-carbaldehyde and 1,3-thiazolidine-2,4-dione as starting materials, the title compound was obtained. It was.

HPLC: 3.02 min. LC-MS: M / Z ESI: 1.17 min, 246.17 (M-1). ¹ H NMR: (DMSOd6) δ 12.58 (br. S, 1 H), 8.07 (m, 2 H), 7.82 (d, J = 9 Hz, 1 H), 7.40 (s, 1 H).

Example 109 5-2- (methyl-benzofuran-6-ylmethylene) -thiazolidine-2,4-dione

General described in Example 1 using 2-methyl-5- [1,3] dioxolan-2-yl-benzofuran (intermediate 72) and 1,3-thiazolidine-2,4-dione as starting materials According to the method and purified by reverse phase HPLC (solvent gradient H ₂ O / CH ₃ CN 0.1% TFA) to afford the title compound.

HPLC: 3.65 min, 90.75%. LC-MS: M / Z ESI: 1.65 min, 258.21 (M-1). ¹ H NMR: (DMSOd6) δ 12.45 (sl, 1H), 7.88 (s, 1H), 7.77 (d, 1H, J = 1.5 Hz), 7.64 (d, 1H, J = 8.6 Hz), 7.47 ( dd, 1H, J = 8.6, 1.5 Hz), 6.69 (s, 1H), 2.37 (s, 3H).

Example 110: 5- (2-carboxymethyl-benzofuran-6-ylmethylene) -thiazolidine-2,4-dione

Example 1, using 5- [1,3] dioxolan-2-yl-benzofuran-2-carboxylic acid methyl ester (intermediate 73) and 1,3-thiazolidine-2,4-dione as starting materials Following the general method described and purified by reverse phase HPLC (solvent gradient H ₂ O / CH ₃ CN 0.1% TFA) to afford the title compound.

HPLC: 3.32 min, 92.06%. LC-MS: M / Z ESI: 1.51 min, 302.19 (M-1). ¹ H NMR: (DMSOd6) δ 12.52 (sl, 1H), 7.97 (d, 1H, J = 1.5 Hz), 7.82 (m, 3H), 7.69 (dd, 1H, J = 8.6, 1.5 Hz), 3.90 (s, 3 H).

Example 111 5- (3-Bromo-2-fluoro-2,3-dihydro-benzofuran-6-ylmethylene) -thiazolidine-2,4-dione

Following the general method described in Example 1, using 3-bromo-2-fluoro-benzofuran-5-carbaldehyde (intermediate 74) and 1,3-thiazolidine-2,4-dione as starting materials Purification by reverse phase HPLC (solvent gradient H ₂ O / CH ₃ CN 0.1% TFA) afforded the title compound.

HPLC: 3.66 min, 92.37%. LC-MS: M / Z ESI: 1.56 min, 343.09 (M-1). ¹ H NMR: (DMSO-d6) δ 12.82 (sl, 1H), 8.00 (d, 1H, J = 1.8 Hz), 7. 88 (dd, 1H, J = 8.5, 1.8 Hz), 7.55 (d, 1H , J = 8.5 Hz), 7.03 (d, 1H, ² J _HF = 59.5 Hz), 6.20 (d, 1H, ³ J _HF = 15.3 Hz). ¹⁹ F NMR: (DMSOd6) δ-114.66.

Example 112 5- (2-Fluoro-benzofuran-6-ylmethylene) -thiazolidine-2,4-dione

Example 1, described as starting materials of 2-fluoro-5- [1,3] dioxolan-2-yl-benzofuran (intermediate 75) and 1,3-thiazolidine-2,4-dione Following the usual method and purified by reverse phase HPLC (solvent gradient H ₂ O / CH ₃ CN 0.1% TFA) to afford the title compound.

HPLC: 3.67 min, 99.47%. LC-MS: M / Z ESI: 1.51 min, 262.14 (M-1). ¹ H NMR: (DMSO-d 6) δ 12.04 (sl, 1H), 7.89 (d, 1H, J = 1.5 Hz), 7.83 (d, 1H, J = 1.5 Hz), 7.73 (d, 1H, J = 8.6 Hz), 7.55 (dd, 1H, J = 8.6, 1.5 Hz), 6.47 (d, 1H, ³ J _HF = 6.4 Hz). ¹⁹ F NMR: (DMSOd6) δ-111.28, -112.18.

Example 113: Preparation of a Pharmaceutical Formulation

The following formulation examples represent, but are not limited to, representative pharmaceutical compositions in accordance with the present invention.

Formulation 1-Tablet

Compounds of formula (I) were mixed as dry powder with dry gelatin binder in approximately 1: 2 weight ratio. A small amount of magnesium stearate was added as a lubricant. In a tablet machine the mixture was formed into 240-270 mg tablets (80-90 mg of active azolidinone compound per tablet).

Formulation 2-capsules

Compounds of formula (I) were mixed as dry powder with starch diluent in approximately 1: 1 weight ratio. The mixture was filled into 250 mg capsules (125 mg of active azolidinone compound per capsule).

Formulation 3-Liquid

Compound of formula (I) (1250 mg), sucrose (1.75 g) and xanthan gum (4 mg) were combined and No. It was passed through a 10 mesh US sieve and then mixed in a pre-made aqueous solution of microcrystalline cellulose and sodium carboxymethyl cellulose (11:89, 50 mg). Sodium benzoate (10 mg), flavor, and colorant were diluted with water and added with stirring. Sufficient water was then added to the product to bring the total volume to 5 mL.

Formulation 4-Tablet

Compounds of formula (I) were mixed as dry powder with dry gelatin binder in approximately 1: 2 weight ratio. A small amount of magnesium stearate was added as lubricant. In a purifier the mixture was formed into 450-900 mg tablets (150-300 mg of active azolidinone compound).

Formulation 5-injection

The compound of formula (I) was dissolved in an injectable aqueous medium of buffered sterile saline to a concentration of approximately 5 mg / ml.

Example 114 Biological Assays

The following assays can be performed on the compounds of the present invention:

a) High Throughput PI3K lipid kinase assay (binding assay):

The assay combines a dose of neomycin (polycation antibiotic) that binds phospholipids with high affinity and specificity and scintillation proximity assay technology (SPA, Amersham). Scintillance proximity measurements are based on the properties of weakly emitting isotopes (eg ³ H, ¹²⁵ I, ³³ P). SPA beads coated with neomycin allow for the detection of phosphorylated lipid substrates after incubation with recombinant PI3K and radioactive ATP in the same well, by trapping radiophospholipids in SPA beads through their specific binding to neomycin .

384 well MTP containing 5 μl of test compound of formula (I) (soluble in 6% DMSO: concentration of test compound is 100, 30, 10, 3, 1, 0.3, 0.1, 0.03, 0.01, 0.001 μM) To the following analytical components were added. 1) Human recombinant GST-PI3Kγ (in Hepes 40 mM, pH 7.4, 1 mM DTT and 5% ethylene glycol) 2) 10 μl lipid micelle and 3) [ ³³ P] γ-ATP 45 μM / in kinase buffer (Hepes 40 mM, pH 7.4 60 nCi, MgCl ₂ 30 mM, DTT 1 mM, β-glycerophosphate 1 mM, Na ₃ VO ₄ 100 μM, Na bile salt 0.3%). After gentle incubation for 180 minutes at room temperature, the reaction was terminated by the addition of 60 μl of a solution containing 100 μg of neomycin-coated PVT SPA beads in PBS containing 10 mM ATP and 5 mM EDTA. Incubate further for 60 minutes at room temperature with gentle stirring to allow phospholipid binding to neomycin-SPA beads. After precipitation of neomycin-coated PVT SPA beads at 1500 xg for 5 minutes, the radioactive PtdIns (3) P was quantified by scintillation counting on a Wallac MicroBeta ™ plate counter.

Values shown for PI3Kγ are the amount necessary to achieve IC ₅₀ (μM), ie 50% inhibition of the target. These values indicate significant efficacy of the azolidinone-vinyl conjugated-benzene compounds on PI3Kγ.

Compounds tested according to formula (I) have an inhibition (PI ₅₀ ) to PI3Kγ of less than 2 μM, more preferably less than or equal to 1 μM.

Examples of inhibitory activity against test compounds 41, 61, 66, 73, 107 and 110 are listed in Table 1.

IC ₅₀ values of azolidinone-vinyl conjugated-benzene derivatives for PI3K _γ Example No PI3Kγ, IC ₅₀ (μM) 41 <1 61 <1 66 <1 73 <1 103 <1 107 <1 110 <1

b) Enzyme-Linked Immunosorbent Assay (ELISA) to monitor PI3K inhibition:

Measurement of Akt / PKB Phosphorylation in Macrophages After C5a Stimulation:

Raw 264: Raw 264-7 macrophages (cultivated in DMEM-F12 medium containing 10% fetal bovine serum and homeostasis) were plated at 96 MTP at 20000 cells / well for 24 hours prior to cell stimulation. Cells were serum starved for 2 hours and pretreated with inhibitor for 20 minutes before stimulation with Complement 5a (C5a; a well-known chemokine that stimulates the cells used) for 5 minutes. After stimulation, cells were fixed with 4% formaldehyde for 20 minutes and washed three times with PBS (PBS / Triton) containing 1% Triton X-100. Endogenous peroxidase was blocked by 20 min incubation in 0.6% H ₂ O ₂ and 0.1% sodium azide in PBS / Triton and washed three times with PBS / Triton. Cells are then blocked by incubating for 60 minutes with 10% fetal bovine serum in PBS / Triton. Phosphorylated Akt / PKB was then 4 ° C. with a first antibody (antiphosphorine phosphate 473 Akt IHC, cell signaling) diluted 800-fold with PBS / Triton containing 5% bovine serum albumin (BAS). Detected by incubation overnight. After washing three times with PBS / Triton, cells were incubated for 60 minutes with peroxidase binding goat-anti-rabbit antibody (1/400 dilution in PBS / Triton, containing 5% BAS) and three times with PBS / Triton Washed, washed twice with PBS and incubated for 20 min in 100 μl of substrate reagent solution (R & D) again. Add 50 μl of 1M H ₂ SO 4 to terminate the reaction and observe absorbance at 450 nm.

The values shown reflect the percent inhibition of AKT phosphorylation compared to the reference level. These values indicate a clear effect of azolidinone-vinyl conjugated-benzene compounds on the activation of AKT phosphorylation in macrophages.

The compounds of Examples 1, 19, 66 and 107 completely (nearly 100%) inhibit C5a-mediated AKT phosphorylation when used at 10 μM. Examples 17, 19 or 73 inhibit 95% C5a-mediated AKT phosphorylation when used at 1 μM.

Claims (37)

Inflammation, comprising an optically active form selected from a compound of formula (I), or a geometric isomer, or diastereomer, enantiomer or racemic form thereof, or a pharmaceutically acceptable salt thereof Therapeutic Agents:

Wherein A is dioxol, dioxin, dihydrofuran, (dihydro) furanyl, (dihydro) oxazinyl, pyridinyl, isoxazolyl, oxazolyl, (dihydro) naphthalenyl, pyrimididi Nil, triazolyl, imidazolyl, pyrazinyl, thiazolidinyl, thiadiazolyl and oxdiazolyl; X is S; Y ¹ and Y ² are both O; Z is O; R ¹ is H; R ² is H, halogen, amino, C ₁ -C ₆ -alkyl, C ₂ -C ₆ -alkenyl, C ₂ -C ₆ -alkynyl, C ₁ -C ₆ -alkyl carboxy, C ₁ -C _6- Alkyl C ₁ -C ₆ -alkoxycarbonyl, C ₁ -C ₆ -alkyl aminocarbonyl, C ₁ -C ₆ -alkyl amino, phenyl, heterocycloalkyl, wherein the heterocycloalkyl is pyrrolidine, piperi Dine, piperazine, 1-methylpiperazine or morpholine), C ₁ -C ₆ -alkyl phenyl, C ₂ -C ₆ -alkenyl phenyl, C ₂ -C ₆ -alkynyl phenyl and carboxy Selected from the group; n is 0, 1 or 2.) delete delete delete delete delete The method of claim 1, n is 1 or 2, and R ¹ and R ² are both hydrogen. The method of claim 1, X is S, Y ¹ and Y ² are both oxygen and n is 0. delete delete delete delete delete delete delete delete delete delete Thiazolidinone-vinyl conjugate-benzene of formula (II-a)

(II-a) Wherein A is dioxol, dioxin, dihydrofuran, (dihydro) furanyl, (dihydro) oxazinyl, pyridinyl, isoxazolyl, oxazolyl, (dihydro) naphthalenyl, pyrimididi Nil, triazolyl, imidazolyl, pyrazinyl, thiazolidinyl, thiadiazolyl and oxdiazolyl; R ² is H, halogen, amino, C ₁ -C ₆ -alkyl, C ₂ -C ₆ -alkenyl, C ₂ -C ₆ -alkynyl, C ₁ -C ₆ -alkyl carboxy, C ₁ -C _6- Alkyl C ₁ -C ₆ -alkoxycarbonyl, C ₁ -C ₆ -alkyl aminocarbonyl, C ₁ -C ₆ -alkyl amino, phenyl, heterocycloalkyl, wherein the heterocycloalkyl is pyrrolidine, piperi Dine, piperazine, 1-methylpiperazine or morpholine), C ₁ -C ₆ -alkyl phenyl, C ₂ -C ₆ -alkenyl phenyl, C ₂ -C ₆ -alkynyl phenyl and carboxy Selected from the group.) Thiazolidinone-vinyl conjugated-benzene of formula (II), or an optically active form selected from geometric isomers, or diastereomers, enantiomers or racemic forms thereof, or a pharmaceutically acceptable thereof Possible salts:

(II) Wherein Y ¹ is O; Z is O; R ¹ is H, CN, carboxy, acyl, C ₁ -C ₆ -alkoxy, halogen, hydroxy, acyloxy, C ₁ -C ₆ -alkyl carboxy, C ₁ -C ₆ -alkyl acyloxy, C ₁ -C ₆ -alkyl alkoxy, alkoxycarbonyl, C ₁ -C ₆ -alkyl alkoxycarbonyl, aminocarbonyl, C ₁ -C ₆ -alkyl aminocarbonyl, acylamino, C ₁ -C ₆ -alkyl acylamino, ureido , C ₁ -C ₆ -alkyl ureido, amino, C ₁ -C ₆ -alkyl amino, ammonium, sulfonyloxy, C ₁ -C ₆ -alkyl sulfonyloxy, sulfonyl, C ₁ -C ₆ -alkyl sulfonate Phonyl, sulfinyl, C ₁ -C ₆ -alkyl sulfinyl, sulfanyl, C ₁ -C ₆ -alkyl sulfanyl, sulfonylamino, C ₁ -C ₆ -alkyl sulfonylamino or carbamate; R ² is H, halogen, amino, C ₁ -C ₆ -alkyl, C ₂ -C ₆ -alkenyl, C ₂ -C ₆ -alkynyl, C ₁ -C ₆ -alkyl carboxy, C ₁ -C _6- Alkyl C ₁ -C ₆ -alkoxycarbonyl, C ₁ -C ₆ -alkyl aminocarbonyl, C ₁ -C ₆ -alkyl amino, phenyl, heterocycloalkyl, wherein the heterocycloalkyl is pyrrolidine, piperi Dine, piperazine, 1-methylpiperazine or morpholine), C ₁ -C ₆ -alkyl phenyl, C ₂ -C ₆ -alkenyl phenyl, C ₂ -C ₆ -alkynyl phenyl, or carboxy; n is 0 or 1) delete 21. The method of claim 20, R ¹ is C ₁ -C ₆ -alkyl, C ₁ -C ₆ -alkyl aryl, aryl, C ₃ -C ₈ -cycloalkyl or heterocycloalkyl, C ₁ -C ₆ -alkyl aryl, C ₂ -C _6- Selected from thiazolidinone-vinyl conjugated-benzene, or geometric isomers, or diastereomers, enantiomers or racemic forms thereof, characterized in that they are alkenyl-aryl or C ₂ -C ₆ -alkynyl aryl. In optically active form, or a pharmaceutically acceptable salt thereof. Thiazolidinone-vinyl conjugated-benzene of formula (III) Possible salts:

Wherein R ¹ is H, CN, carboxy, acyl, C ₁ -C ₆ -alkoxy, halogen, hydroxy, acyloxy, C ₁ -C ₆ -alkyl carboxy, C ₁ -C ₆ -alkyl acyoxy, C ₁ -C ₆ -alkyl alkoxy, alkoxycarbonyl, C ₁ -C ₆ -alkyl alkoxycarbonyl, aminocarbonyl, C ₁ -C ₆ -alkyl aminocarbonyl, acylamino, C ₁ -C ₆ -alkyl acyl Amino, ureido, C ₁ -C ₆ -alkyl ureido, amino, C ₁ -C ₆ -alkyl amino, ammonium, sulfonyloxy, C ₁ -C ₆ -alkyl sulfonyloxy, sulfonyl, C ₁ -C ₆ -alkyl sulfonyl, sulfinyl, C ₁ -C ₆ -alkyl sulfinyl, sulfanyl, C ₁ -C ₆ -alkyl sulfanyl, sulfonylamino, C ₁ -C ₆ -alkyl sulfonylamino or carbamate; R ² is H, halogen, amino, C ₁ -C ₆ -alkyl, C ₂ -C ₆ -alkenyl, C ₂ -C ₆ -alkynyl, C ₁ -C ₆ -alkyl carboxy, C ₁ -C _6- Alkyl C ₁ -C ₆ -alkoxycarbonyl, C ₁ -C ₆ -alkyl aminocarbonyl, C ₁ -C ₆ -alkyl amino, phenyl, heterocycloalkyl, wherein the heterocycloalkyl is pyrrolidine, piperi Dine, piperazine, 1-methylpiperazine or morpholine), C ₁ -C ₆ -alkyl phenyl, C ₂ -C ₆ -alkenyl phenyl, C ₂ -C ₆ -alkynyl phenyl, or carboxy .) Thiazolidinone-vinyl junction-benzene of any one of the following formulas (IV), (V) and (VI):

Wherein R ¹ is hydrogen, halogen, cyano, C ₁ -C ₆ -alkyl, C ₁ -C ₆ -alkoxy, acyl or alkoxy carbonyl, R ² is H, halogen, amino, C ₁ -C ₆ -alkyl, C ₂ -C ₆ -alkenyl, C ₂ -C ₆ -alkynyl, C ₁ -C ₆ -alkyl carboxy, C ₁ -C _6- Alkyl C ₁ -C ₆ -alkoxycarbonyl, C ₁ -C ₆ -alkyl aminocarbonyl, C ₁ -C ₆ -alkyl amino, phenyl, heterocycloalkyl, wherein the heterocycloalkyl is pyrrolidine, piperi Dine, piperazine, 1-methylpiperazine or morpholine), C ₁ -C ₆ -alkyl phenyl, C ₂ -C ₆ -alkenyl phenyl, C ₂ -C ₆ -alkynyl phenyl, or carboxy .) 20. The method of claim 19, Thiazolidinone-vinyl conjugated-benzene, selected from the group consisting of: 5- (1,3-benzodioxol-5-ylmethylene) -1,3-thiazolidine-2,4-dione 5- (1,3-benzodioxol-5-ylmethylene) -2-thioxo-1,3-thiazolidin-4-one 5- (2,3-dihydro-1,4-benzodioxin-6-ylmethylene) -1,3-thiazolidine-2,4-dione 5- (2,3-dihydro-1-benzofuran-5-ylmethylene) -1,3-thiazolidine-2,4-dione 5-[(7-methoxy-1,3-benzodioxol-5-yl) methylene-1,3-thiazolidine-2,4-dione 5-[(9,10-dioxo-9,10-dihydroanthracen-2-yl) methylene] -1,3-thiazolidine-2,4-dione (5-[(2,2-difluoro-1,3-benzodioxol-5-yl) methylene] -1,3-thiazolidine-2,4-dione (5Z) -5- (1,3-dihydro-2-benzofuran-5-ylmethylene) -1,3-thiazolidine-2,4-dione 5- (1-benzofuran-5-ylmethylene) -1,3-thiazolidine-2,4-dione 5-[(4-methyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6-yl) methylene] -1,3-thiazolidine-2,4-dione 5- (1,3-benzodioxol-5-ylmethylene) -2-imino-1,3-thiazolidin-4-one 5-quinolin-6-ylmethylene-thiazolidine-2,4-dione 5-quinolin-6-ylmethylene-2-thioxo-thiazolidin-4-one 2-imino-5-quinolin-6-ylmethylene-thiazolidin-4-one 5- (3-Methyl-benzo [d] isoxazol-5-ylmethylene) -thiazolidine-2,4-dione 5- (4-phenyl-quinazolin-6-ylmethylene) -thiazolidine-2,4-dione 5- (4-Dimethylamino-quinazolin-6-ylmethylene) -thiazolidine-2,4-dione 5-[(4-aminoquinazolin-6-yl) methylene] -1,3-thiazolidine-2,4-dione 5-[(4-piperidin-1-ylquinazolin-6-yl) methylene] -1,3-thiazolidine-2,4-dione 5-[(4-morpholin-4-ylquinazolin-6-yl) methylene] -1,3-thiazolidine-2,4-dione 5-{[4- (benzylamino) quinazolin-6-yl] methylene} -1,3-thiazolidine-2,4-dione 5-{[4- (diethylamino) quinazolin-6-yl] methylene} -1,3-thiazolidine-2,4-dione 5-({4-[(pyridin-2-ylmethyl) amino] quinazolin-6-yl} methylene) -1,3-thiazolidine-2,4-dione 5-({4-[(pyridin-3-ylmethyl) amino] quinazolin-6-yl} methylene-1,3-thiazolidine-2,4-dione Ethyl 1- {6-[(2,4-dioxo-1,3-thiazolidine-5-ylidene) methyl] quinazolin-4-yl} piperidine-3-carboxylate Ethyl 1- {6-[(2,4-dioxo-1,3-thiazolidine-5-ylidene) methyl] quinazolin-4-yl} piperidine-4-carboxylate tert-butyl1- {6-[(2,4-dioxo-1,3-thiazolidin-5-ylidene) methyl] quinazolin-4-yl] -L-prolinate 5-{[4- (4-methylpiperazin-1-yl) quinazolin-6-yl] methylene} -1,3-thiazolidine-2,4-dione 5-{[4- (4-pyrimidin-2-ylpiperazin-1-yl) quinazolin-6-yl] methylene-1,3-thiazolidine-2,4-dione 5-({4- [4- (4-fluorophenyl) piperidin-1-yl] quinazolin-6-yl} methylene-1,3-thiazolidine-2,4-dione 5-{[4- (4-benzylpiperidin-1-yl) quinazolin-6-yl] methylene} -1,3-thiazolidine-2,4-dione 5 ({4- [4- (2-phenylethyl) piperidin-1-yl] quinazolin-6-yl} methylene) -1,3-thiazolidine-2,4-dione 5-{[4- (4-methylpiperidin-1-yl) quinazolin-6-yl] methylene} -1,3-thiazolidine-2,4-dione 5-{[4- (4-hydroxypiperidin-1-yl) quinazolin-6-yl] methylene} -1,3-thiazolidine-2,4-dione 1- [6- (2,4-Dioxo-thiazolidine-5-ylidenemethyl) -quinazolin-4-yl] -piperidine-4-carboxylic acid 1- [6- (2,4-Dioxo-thiazolidine-5-ylidenemethyl) -quinazolin-4-yl] -piperidine-3-carboxylic acid 1- [6- (2,4-Dioxo-thiazolidine-5-ylidenemethyl) -quinazolin-4-yl] -pyrrolidine-2-carbosylic acid 5- (4-Methylamino-quinazolin-6-ylmethylene) -thiazolidine-2,4-dione 5- (4-methoxy-quinazolin-6-ylmethylene) -thiazolidine-2,4-dione 2-imino-5- (4-methylamino-quinazolin-6-ylmethylene) -thiazolidin-4-one 2-imino-5- (4-piperidin-quinazolin-6-ylmethylene) -thiazolidin-4-one 2-imino-5- (4-dimethylamino-quinazolin-6-ylmethylene) -thiazolidin-4-one 5- (2-Methyl-2H-benzotriazol-5-ylmethylene) -thiazolidine-2,4-dione 5- (3-Methyl-3H-benzotriazol-5-ylmethylene) -thiazolidine-2,4-dione 5- (3-ethyl-3H-benzoimidazol-5-ylmethylene) -thiazolidine-2,4-dione 5-{[1- (4-phenylbutyl) -1H-benzimidazol-6-yl] methylene} -1,3-thiazolidine-2,4-dione 5-[(1-prop-2-yn-1-yl-1H-benzimidazol-6-yl) methylene] -1,3-thiazolidine-2,4-dione 5-[(1- {2- [4- (trifluoromethyl) phenyl] ethyl} -1H-benzimidazol-6-yl) methylene] -1,3-thiazolidine-2,4-dione 5-({1- [2- (4-hydroxyphenyl) ethyl] -1H-benzimidazol-6-yl} methylene) -1,3-thiazolidine-2,4-dione Methyl 4- {6-[(2,4-dioxo-1,3-thiazolidine-5-ylidene) methyl] -1H-benzimidazol-1-yl} cyclohexanecarboxylate 5-({1- [2- (5-methoxy-1H-indol-3-yl) ethyl] -1H-benzimidazol-6-yl} methylene) -1,3-thiazolidine-2,4 Dion 5-({1-[(1-methyl-1H-pyrazol-4-yl) methyl] -1H-benzimazol-6-yl} methylene) -1,3-thiazolidine-2,4-dione 5-({1- [2- (3,4-dimethoxyphenyl) ethyl] -1H-benzimidazol-6-yl} methylene) -1,3-thiazolidine-2,4-dione 5 ({1- [2- (4-phenoxyphenyl) ethyl] -1H-benzimidazol-6-yl} methylene) -1,3-thiazolidine-2,4-dione 5-({1- [4- (trifluoromethyl) benzyl] -1H-benzimidazol-6-yl} methylene) -1,3-thiazolidine-2,4-dione 4- {6-[(2,4-dioxo-1,3-thiazolidine-5-ylidene) methyl] -1H-benzimidazol-1-yl} cyclohexanecarboxylic acid 5-[(1-isobutyl-1H-benzimidazol-6-yl) methylene] -1,3-thiazolidine-2,4-dione 5-({1- [2- (1,3-benzodioxol-4-yl) ethyl] -1H-benzimidazol-6-yl} methylene) -1,3-thiazolidine-2,4- Dion 5-({1- [2- (2-phenoxyphenyl) ethyl] -1H-benzimidazol-6-yl} methylene) -1,3-thiazolidine-2,4-dione 5-{[1- (3,3-diphenylpropyl) -1H-benzimidazol-6-yl] methylene} -1,3-thiazolidine-2,4-dione 5-{[1- (2-methoxybenzyl) -1H-benzimidazol-6-yl] methylene} -1,3-thiazolidine-2,4-dione 5-{[1- (3-furylmethyl) -1H-benzimidazol-6-yl] methylene} -1,3-thiazolidine-2,4-dione 5-[(1-propyl-1H-benzimidazol-6-yl] methylene} -1,3-thiazolidine-2,4-dione 5-quinoxaline-6-ylmethylene-thiazolidine-2,4-dione 5-quinoxalin-6-ylmethylene-2-thioxo-thiazolidin-4-one 2-imino-5-quinoxalin-6-ylmethylene-thiazolidin-4-one 5-benzothiazol-6-ylmethylene-thiazolidine-2,4-dione 5- (3-Methyl-benzofuran-5-ylmethylene) -thiazolidine-2,4-dione 5- (2-Bromo-3-methyl-benzofuran-5-ylmethylene) -thiazolidine-2,4-dione 5- (3-Bromo-benzofuran-5-ylmethylene) -thiazolidine-2,4-dione 3- [5- (2,4-Dioxo-thiazolidine-5-ylidenemethyl) -benzofuran-3-yl] -acrylic acid ethyl ester 3- [5- (2,4-Dioxo-thiazolidine-5-ylidenemethyl) -benzofuran-3-yl] -acrylic acid 5- [3- (3-Oxo-3-piperidin-1-yl-propenyl) -benzofuran-5-ylmethylene] -thiazolidine-2,4-dione Methyl 1-((3- {5-[(2,4-dioxo-1,3-thiazolidin-5-ylidene) methyl] -benzofuran-3-yl} prop-2-enoyl) Prolinate Methyl 1-((3- {5-[(2,4-dioxo-1,3-thiazolidin-5-ylidene) methyl] -1-benzofuran-3-yl} prop-2-ene O'Neill) -D-Prolinate (5-({3-[(3-oxo-3-pyrrolidin-1-ylprop-1-en-1-yl] -1-benzofuran-5-yl} methylene) -1,3- Thiazolidine-2,4-dione 5-({3- [3-morpholin-4-yl-3-oxoprop-1-en-1-yl] -1-benzofuran-5-yl} methylene) -1,3-thiazolidine -2,4-dione Methyl 1- (3- {5-[(2,4-dioxo-1,3-thiazolidin-5-ylidene) methyl] -1-benzofuran-3-yl} prop-2-enoyl ) -L-prolinate N-cyclohexyl-3- {5-[(2,4-dioxo-1,3-thiazolidin-5-ylidene) methyl] -1-benzofuran-3-yl} -N-methylacrylic amides 3- {5-[(2,4-dioxo-1,3-thiazolidine-5-ylidene) methyl] -1-benzofuran-3-yl} -N-ethyl-N- (2-hydr Oxyethyl) acrylamide N-cyclobutyl-3- {5-[(2,4-dioxo-1,3-thiazolidin-5-ylidene) methyl] -1-benzofuran-3-yl} acrylamide 5-({3- [3-azetidin-1-yl-3-oxoprop-1-en-1-yl] -1-benzofuran-5-yl} methylene) -1,3-thiazolidine -2,4-dione 5-({3- [3- (1,3-Dihydro-2H-isoindol-2-yl) -3-oxoprop-1-en-1-yl] -1-benzofuran-5-yl Methylene) -1,3-thiazolidine-2,4-dione 5-({3- [3-Azepan-1-yl-3-oxoprop-1-en-1-yl] -1-benzofuran-5-yl} methylene-1,3-thiazolidine- 2,4-dione 3- {5-[(2,4-dioxo-1,3-thiazolidine-5-ylidene) methyl] -1-benzofuran-3-yl} -N-piperidin-1-ylacrylic amides 3- {5-[(2,4-dioxo-1,3-thiazolidine-5-ylidene) methyl] -1-benzofuran-3-yl} -N- (pyridin-3-ylmethyl) Acrylamide N-cyclohexyl-3- {5-[(2,4-dioxo-1,3-thiazolidin-5-ylidene) methyl] -1-benzofuran-3-yl} acrylamide 5-({3- [3- (4-methylpiperazin-1-yl) -3-oxoprop-1-en-1-yl] -1-benzofuran-5-yl} methylene) -1, 3-thiazolidine-2,4-dione N-cycloheptyl-3- {5-[(2,4-dioxo-1,3-thiazolidin-5-ylidene) methyl] -1-benzofuran-3-yl} acrylamide 5-({3- [3- (2,5-Dihydro-1H-pyrrol-1-yl) -3-oxoprop-1-en-1-yl] -1-benzofuran-5-yl} Methylene) -1,3-thiazolidine-2,4-dione N-cyclopentyl-3- {5-[(2,4-dioxo-1,3-thiazolidin-5-ylidene) methyl] -1-benzofuran-3-yl} acrylamide 3- [5- (2,4-Dioxo-thiazolidine-5-ylidenemethyl) -benzofuran-3-yl] -propionic acid ethyl ester 3- [5- (2,4-Dioxo-thiazolidine-5-ylidenemethyl) -benzofuran-3-yl] -propionic acid 5- [3- (3-Oxo-3-piperidin-1-yl-propyl) -benzofuran-5-ylmethylene] -thiazolidine-2,4-dione 6- (2,4-dioxo-thiazolidine-5-ylidenemethyl) -2,3-dihydro-benzo [1,4] oxazine-4-carboxylic acid tert-butyl ester 5- (3,4-Dihydro-2H-benzo [1,4] oxazin-6-ylmethylene) -thiazolidine-2,4-dione 5- (4-benzoyl-3,4-dihydro-2H-benzo [1,4] oxazin-6-ylmethylene) -thiazolidine-2,4-dione 5- (4-acetyl-3,4-dihydro-2H-benzo [1,4] oxazin-6-ylmethylene) -thiazolidine-2,4-dione 6- (2,4-dioxo-thiazolidine-5-ylidenemethyl) -benzo [1,4] oxazine-4-carboxylic acid tert-butyl ester [6- (2,4-Dioxo-thiazolidine-5-ylidenemethyl) -3-oxo-2,3-dihydro-benzo [1,4] -oxazin-4-yl] -methyl acetate ester N-benzyl-2- [6- (2,4-dioxo-thiazolidine-5-ylidenemethyl) -3-oxo-2,3-dihydro-benzo [1,4] oxazine-4- General] -acetamide 5- (4-Butyl-3-oxo-3,4-dihydro-2H-benzo [1,4] oxazin-6-ylmethylene) -thiazolidine-2,4-dione 5- (4-benzyl-3-oxo-3,4-dihydro-2H-benzo [1,4] oxazin-6-ylmethylene) -thiazolidine-2,4-dione 5- (2-Chloro-benzofuran-5-ylmethylene) -thiazolidine-2,4-dione 5- (3-Amino-benzo [d] isoxazol-5-ylmethylene) -thiazolidine-2,4-dione 5- (3-phenylethynyl-benzofuran-5-ylmethylene) -thiazolidine-2,4-dione 5-benzo [1,2,5] thiadiazol-5-ylmethylene-thiazolidine-2,4-dione 5-benzo [1,2,5] oxodiazol-5-ylmethylene-thiazolidine-2,4-dione 5- (2-Methyl-benzofuran-6-ylmethylene) -thiazolidine-2,4-dione 5- (2-carboxymethyl-benzofuran-6-ylmethylene) -thiazolidine-2,4-dione 5- (3-Bromo-2-fluoro-2,3-dihydro-benzofuran-6-ylmethylene) -thiazolidine-2,4-dione 5- (2-Fluoro-benzofuran-6-ylmethylene) -thiazolidine-2,4-dione. 20. A process for the preparation of a medicament comprising contacting a thiazolidinone-vinyl conjugated-benzene according to claim 19 with at least one pharmaceutically acceptable additive. A pharmaceutical composition comprising at least one thiazolidinone-vinyl conjugated-benzene according to claim 19 and a pharmaceutically acceptable diluent, diluent or excipient. A medicament for the treatment of inflammation comprising thiazolidinone-vinyl conjugated-benzene according to claim 19. delete delete delete delete delete delete A process for preparing a thiazolidinone-vinyl conjugated-benzene of formula (II) according to claim 20 comprising the following steps:

(Wherein R ¹ , R ² , Y ¹ , Z and n are as defined in formula (II) above). A process for preparing a thiazolidinone-vinyl conjugated-benzene of formula (III) according to claim 23 comprising the following steps:

(Wherein R ¹ , R ² are as defined in formula (III) above, Y ¹ is O, S or N.) Pharmaceutically acceptable diluents, diluents or excipients, and optically active selected from at least one compound of formula (I), or a geometric isomer, or diastereomer, enantiomer or racemic form thereof A pharmaceutical composition for treating inflammation, comprising a form, or a pharmaceutically acceptable salt thereof:

(I) Wherein A is dioxol, dioxin, dihydrofuran, (dihydro) furanyl, (dihydro) oxazinyl, pyridinyl, isoxazolyl, oxazolyl, (dihydro) naphthalenyl, pyrimididi Nil, triazolyl, imidazolyl, pyrazinyl, thiazolidinyl, thiadiazolyl and oxdiazolyl; X is S; Y ¹ and Y ² are both O; Z is O; R ¹ is H; R ² is H, halogen, amino, C ₁ -C ₆ -alkyl, C ₂ -C ₆ -alkenyl, C ₂ -C ₆ -alkynyl, C ₁ -C ₆ -alkyl carboxy, C ₁ -C _6- Alkyl C ₁ -C ₆ -alkoxycarbonyl, C ₁ -C ₆ -alkyl aminocarbonyl, C ₁ -C ₆ -alkyl amino, phenyl, heterocycloalkyl, wherein the heterocycloalkyl is pyrrolidine, piperi Dine, piperazine, 1-methylpiperazine or morpholine), C ₁ -C ₆ -alkyl phenyl, C ₂ -C ₆ -alkenyl phenyl, C ₂ -C ₆ -alkynyl phenyl and carboxy Selected from the group; n is 0, 1 or 2.)